Stereoselective preparation of substituted piperidines

ABSTRACT

Novel processes are disclosed for the stereoselective preparation of substituted piperidine derivatives of the formulae ##STR1## wherein R 1  and R 2  are defined as below, useful as substance P receptor antagonists and in treating diseases mediated by an excess of substance P.

This is the national stage application of PCT applicationPCT/US92/00065, filed Jan. 14, 1992, which published as WO 92/17449 onOct. 15, 1992, and was a continuation-in-part application of U.S. patentapplication Ser. No. 07/675,244, filed Mar. 26, 1991, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to novel processes for the stereoselectivepreparation of substituted piperidine derivatives.

The substituted piperidines and related compounds that can be preparedby the processes of this invention are substance P receptor antagonistsand are therefore useful in treating diseases mediated by an excess ofsubstance P.

Substance P is a naturally occurring undecapeptide belonging to thetachykinin family of peptides, the latter being named for their promptstimulatory action on smooth muscle tissue. More specifically, substanceP is a pharmacologically-active neuropeptide that is produced in mammals(having originally been isolated from gut) and possesses acharacteristic amino acid sequence that is illustrated by D. F. Veber etal. in U.S. Pat. No. 4,680,283.

The wide involvement of substance P and other tachykinins in thepathophysiology of numerous diseases has been amply demonstrated in theart. For instance, substance P has been shown to be involved in thetransmission of pain or migraine (see B. E. B. Sandberg et al., Journalof Medicinal Chemistry, Vol. 25, p. 1009 (1982)), as well as in centralnervous system disorders such as anxiety and schizophrenia, inrespiratory and inflammatory diseases such as asthma and rheumatoidarthritis, respectively, in rheumatic diseases such as fibrositis, andin gastrointestinal disorders and diseases of the GI tract, such asulcerative colitis and Crohn's disease, etc. (see D. Regoli in "Trendsin Cluster Headache," edited by F. Sicuteri et al., Elsevier ScientificPublishers, Amsterdam, 1987, pp. 85-95).

Several of the substituted piperidines and related compounds that can beprepared by the methods of this invention are claimed in PCT PatentApplication PCT/US 90/00116, filed Jan. 4, 1990, U.S. patent applicationSer. No. 07/717,943, filed Jun. 20, 1991 and U.S. patent applicationSer. No. 07/724,268, entitled "3-Aminopiperidine Derivatives and RelatedNitrogen Containing Hetercycles" and filed Jul. 1, 1991, all of whichare assigned in common with the present application. Other methods forpreparing such compounds referred to in the United State PatentApplication entitled "Preparation of Substituted Piperidines", which wasfiled in Nov. 27, 1991 and is assigned in common with the presentapplication.

SUMMARY OF THE INVENTION

The present invention relates to a process for preparing a compound ofthe formula ##STR2## wherein R¹ is aryl selected from indanyl, phenyland naphthyl; heteroaryl selected from thienyl, furyl, pyridyl andquinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of saidcarbon atoms may optionally be replaced by nitrogen, oxygen or sulfur;wherein each of said aryl and heteroaryl groups may optionally besubstituted with one or more substituents, and said (C₃ -C₇)cycloalkylmay optionally be substituted with one or two substituents, saidsubstituents being independently selected from chloro, fluoro, bromo,iodo, nitro, (C₁ -C₁₀)alkyl optionally substituted from one to threefluoro groups, (C₁ -C₁₀)alkoxy optionally substituted with from one tothree fluoro groups, amino, (C₁ -C₁₀)alkyl-S--, ##STR3## (C₁-C₁₀)alkyl-SO₂ --, phenyl, phenoxy, (C₁ -C₁₀)alkyl-SO₂ NH--, (C₁-C₁₀)alkyl-SO₂ NH--(C₁ -C₁₀)alkyl-, (C₁ -C₁₀)alkylamino-di(C₁-C₁₀)alkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, (C₁-C₆)alkylamino, (C₁ -C₆)dialkylamino, ##STR4## wherein the nitrogenatoms of said amino and (C₁ -C₆)alkylamino groups may optionally beprotected with an appropriate protecting group; and R² is thienyl,benzhydryl, naphthyl or phenyl optionally substituted with from one tothree substituents independently selected from chloro, bromo, fluoro,iodo, cycloalkoxy having 3 to 7 carbon atoms, (C₁ -C₁₀)alkyl optionallysubstituted with from one to three fluoro groups and (C₁ -C₁₀)alkoxyoptionally substituted with from one to three fluoro groups, comprisingreacting a compound of the formula ##STR5## wherein R² is defined asabove, with either (a) a compound of the formula ##STR6## wherein R¹ isdefined as above and X is a leaving group (e.g., chloro, bromo, iodo orimidazole), followed by treatment of the resulting amide with a reducingagent, (b) a compound of the formula R¹ CHO, wherein R¹ is defined asabove, in the presence of a reducing agent, or (c) a compound of theformula R¹ CH₂ X, wherein R¹ is defined as above and X is a leavinggroup (e.g., chloro, bromo, iodo, mesylate or tosylate).

As used herein, the term "halo" refers to chloro, bromo, fluoro or iodo.

The compounds of formula I have chiral centers and therefore exist indifferent enantiomeric forms. Formula I, as depicted above, includes alloptical isomers of such compounds, and mixtures thereof.

The present invention also relates to a process for preparing a compoundof the formula I, as depicted above, wherein R¹ and R² are defined asabove, comprising reacting a compound of the formula IV, as depictedabove, wherein R² is defined as above, with a compound of the formula R¹CHO, wherein R¹ is defined above, in the presence of a drying agent orusing an apparatus designed to remove azeotropically the watergenerated, to produce an imine of the formula ##STR7## wherein R¹ and R²are defined as above, and then reacting the imine with a reducing agentto form a compound of the formula I, as depicted above, wherein R¹ andR² are defined as above.

The present invention also relates to a process for preparing a compoundof the formula I, as depicted above, wherein R¹ and R² are defined asabove, comprising reducing a compound of the formula ##STR8## wherein R²is defined as above, to produce a compound of the formula IV, asdepicted above, wherein R² is defined as above, and then converting thecompound of formula IV so formed to a compound of the formula I usingone of the procedures described above.

This invention also relates to a process for preparing a compound of theformula I, as depicted above, wherein R¹ and R² are defined as above,comprising reacting a compound of the formula ##STR9## with hydrogen inthe presence of a metal containing catalyst to form a compound of theformula IV, as depicted above, wherein R² is defined as above, and thenconverting the compound of formula IV so formed to a compound of theformula I using one of the procedures described above.

DETAILED DESCRIPTION OF THE INVENTION

The processes and products of the present invention are illustrated inthe following reaction scheme. Except where otherwise indicated, in thereaction scheme and discussion that follow, formulas I, II, III and IV,and substituents R¹, R² and X are defined as above. ##STR10##

The reaction of a compound of the formula IV with a compound of theformula R¹ CHO to produce a compound of the formula I is typicallycarried out in the presence of a reducing agent such as sodiumcyanoborohydride, sodium triacetoxyborohydride, sodium borohydride,hydrogen and a metal catalyst, zinc and hydrochloric acid, or formicacid at a temperature from about -60° C. to about 50° C. Suitablereaction inert solvents for this reaction include lower alcohols (e.g.,methanol, ethanol and isopropanol), acetic acid and tetrahydrofuran(THF). Preferably, the solvent is acetic acid, the temperature is about25° C., and the reducing agent is sodium triacetoxyborohydride. Thisreaction proceeds to give material in which the addition of the CH₂ R¹sidechain occurs selectively at the 3-amino group, and the isomer offormula I is the only product isolated.

Alternatively, the reaction of a compound of the formula IV with acompound of the formula R¹ CHO may be carried out in the presence of adrying agent or using an apparatus designed to remove azeotropically thewater generated, to produce an imine of the formula ##STR11## which isthen reacted with a reducing agent as described above, preferably withsodium triacetoxyborohydride at about room temperature. The preparationof the imine is generally carried out in a reaction inert solvent suchas benzene, xylene or toluene, preferably toluene, at a temperature fromabout 25° C. to about 110° C., preferably at about the refluxtemperature of the solvent. Suitable drying agents/solvent systemsinclude titanium tetrachloride/dichloromethane titaniumisopropoxide/dichloromethane and molecular sieves/THF. Titaniumtetrachloride/dichloromethane is preferred.

The reaction of a compound of the formula IV with a compound of theformula R¹ CH₂ X is typically carried out in a reaction inert solventsuch as dichloromethane or THF, preferably dichloromethane, at atemperature from about 0° C. to about 60° C., preferably at about 25° C.

The reaction of a compound of the formula IV with a compound of theformula ##STR12## is typically carried out in an inert solvent such astetrahydrofuran (THF) or dichloromethane at a temperature from about-20° C. to about 60° C., preferably in dichloromethane at about 0° C.Reduction of the resulting amide is accomplished by treatment with areducing agent such as borane dimethylsulfide complex, lithium aluminumhydride or diisobutylaluminum hydride in an inert solvent such as ethylether or THF. The reaction temperature may range from about 0° C. toabout the reflux temperature of the solvent. Preferably, the reductionis accomplished using borane dimethylsulfide complex in THF at about 60°C.

Reduction of the pyridine of formula II to form the correspondingpiperidine of formula IV is generally accomplished using either sodiumin alcohol, lithium aluminum hydride/aluminum trichloride, electrolyticreduction or hydrogen in the presence of a metal containing catalyst.The reduction with sodium is generally conducted in a boiling alcohol,preferably butanol, at a temperature from about 20° C. to about thereflux temperature of the solvent, preferably at about 120° C. Thereduction with lithium aluminum hydride/aluminum trichloride is usuallycarried out in ether, THF or dimethoxyethane, preferably ether, at atemperature from about 25° C. to about 100° C., preferably at about roomtemperature. The electrolytic reduction is conducted, preferably, atroom temperature, but temperatures from about 10° C. to about 60° C. arealso suitable.

Hydrogenation in the presence of a metal containing catalyst is thepreferred method of reduction. Suitable hydrogenation catalysts includepalladium, platinum, nickel, platinum oxide and rhodium. The preferredcatalyst for hydrogenation is platinum on carbon. The reactiontemperature may range from about 10° C. to about 50° C., with about 25°C. being preferred. The hydrogenation is generally carried out at apressure from about 1.5 to about 4 atmospheres, preferably at about 3.0atmospheres, in a suitable inert solvent such as acetic acid or a loweralcohol, preferably methanol, with about a stoichiometric quantity ofhydrogen chloride present. When the reduction is carried out viahydrogenation in the presence of a metal containing catalyst, materialof the cis configuration is isolated exclusively and the pyridine ringis reduced selectively as opposed to the 2-phenyl moiety.

The preparation of compounds of the formula IV from the correspondingcompounds of the formula III is accomplished, as indicated above, bytreating the compounds of formula III with hydrogen in the presence of ametal containing catalyst such as platinum or palladium. Generally, thisreaction is conducted in a reaction inert solvent such as acetic acid ora lower alcohol, at a temperature from about 0° C. to about 50° C.Alternatively, the compounds of formula III may be treated with adissolving metal such as lithium or sodium in ammonia at a temperaturefrom about -30° C. to about -78° C., or with a formate salt in thepresence of palladium or with cyclohexene in the presence of palladium.Preferably, the compounds of formula III are treated with hydrogen inthe presence of palladium on carbon in a mixture of methanol/ethanol inwater or methanol/ethanol containing hydrochloric acid at a temperatureof about 25° C. When compounds of the formula III are treated withhydrogen in the presence of a metal containing catalyst, the onlyproducts isolated are the desired compounds of the formula IV. Noproducts derived from cleavage of the alternative benzylic position ofthe piperidine ring (i.e., the bond between the nitrogen at position Iand the carbon at position 2) are observed.

The starting materials of the formulae ##STR13## R¹ CHO and R¹ CH₂ Xthat are used in the above reactions are either commercially availableor obtainable by carrying out standard transformation well known tothose skilled in the art upon commercially available materials.

In each of the above reactions wherein one piperidine derivative isconverted to another piperidine derivative (i.e., III→IV and IV→I), theabsolute stereochemistry about the carbons at positions 2 and 3 of thepiperidine ring is preserved. Therefore, for each such reaction, aracemic mixture or a pure enantiomer may be obtained by using theappropriate starting material having the same stereochemistry.

The resolution of a racemic mixture of a compound of the formula I toprepare the (+) enantiomer of such compound is generally carried outusing methanol, ethanol, or isopropanol, preferably isopropanol, as theorganic reaction inert solvent. Preferably, the resolution is carriedout by combining a racemic mixture of a compound of the formula I and(R)-(-)-mandelic acid in isopropanol, and stirring the mixture to forman optically enriched mandelic acid salt precipitate. The opticallyenriched precipitate is then recrystallized twice from isopropanol,after which the recrystallized precipitate is converted to the free baseof the optically pure compound of formula I by partitioning it betweendichloromethane and an aqueous base such as sodium hydroxide, sodiumbicarbonate or potassium bicarbonate, preferably sodium hydroxide, or bystirring an alcoholic solution of the salt with a basic ion exchangeresin. The free base, which is dissolved in the methylene chloride, canthen be converted to the corresponding hydrochloric acid salt. Isolationof the mandelate may be conducted at temperatures from about 0° C. toabout 40° C. About 25° C. is preferred.

In each of the reactions discussed or illustrated above, pressure is notcritical unless otherwise indicated. Pressures from about 0.5atmospheres to about 5.0 atmospheres are generally acceptable, andambient pressure, i.e., about one atmosphere, is preferred as a matterof convenience.

The compounds of Formula I and their pharmaceutically acceptable saltsexhibit substance P receptor antagonist activity and therefore are ofvalue in the treatment and prevention of a wide variety of clinicalconditions the treatment or prevention of which are effected orfacilitated by a decrease in substance P mediated neurotransmission.Such conditions include inflammatory diseases (e.g., arthritis,psoriasis, asthma and inflammatory bowel disease), anxiety, depressionor dysthymic disorders, colitis, psychosis, pain, allergies such aseczema and rhinitis, chronic obstructive airways disease,hypersensitivity disorders such as poison ivy, vasospastic diseases suchas angina, migraine and Reynaud's disease, fibrosing and collagendiseases such as scleroderma and eosinophilic fascioliasis, reflexsympathetic dystrophy such as shoulder/hand syndrome, addictiondisorders such as alcoholism, stress related somatic disorders,peripheral neuropathy, neuralgia, neuropathological disorders such asAlzheimer's disease, AIDS related dementia, diabetic neuropathy andmultiple sclerosis, disorders related to immune enhancement orsuppression such as systemic lupus erythematosus, and rheumatic diseasessuch as fibrositis. Hence, these compounds are readily adapted totherapeutic use as substance P receptor antagonists for the controland/or treatment of any of the aforesaid clinical conditions in mammals,including humans.

The compounds of the formula I and the pharmaceutically acceptable saltsthereof can be administered via either the oral, parenteral or topicalroutes. In general, these compounds are most desirably administered indosages ranging from about 5.0 mg up to about 1500 mg per day, althoughvariations will necessarily occur depending upon the weight andcondition of the subject being treated and the particular route ofadministration chosen. However, a dosage level that is in the range ofabout 0.07 mg to about 21 mg per kg of body weight per day is mostdesirably employed.

The following examples illustrate the methods and compounds of thepresent invention but do not limit its scope.

As indicated above, the starting materials used in the reaction of thisinvention are either commercially available or obtainable by carryingout standard transformation well known to those skilled in the art uponcommercially available materials. Table 1 below indicates how thealdehydes of the formula R¹ CHO used in the examples were obtained. Thestandard transformations used to prepare these aldehydes are identifiedby one or more lower case letters in the column labelled "ReactionSequence" in Table 1. The letters used to identify such transformationsare explained in the key following Table 1.

                                      TABLE 1                                     __________________________________________________________________________    Preparation of R.sup.1 CHO                                                                                     Reaction*                                    R.sup.1          Starting Material                                                                             Sequence                                     __________________________________________________________________________    2,5-dimethoxyphenyl                                                                            --              commercial                                   4,5-difluoro-2-methoxyphenyl                                                                   3,4-difluoro-methoxybenzene                                                                   a                                            2-chloro-5-fluorophenyl                                                                        --              commercial                                   2-ethoxyphenyl   --              commercial                                   2-hydroxyphenyl  --              commercial                                   3,5-difluoro-2-methoxyphenyl                                                                   2,4-difluoro-methoxybenzene                                                                   a                                            2-chloro-2-fluorophenyl                                                                        --              commercial                                   5-chloro-2-methoxyphenyl                                                                       4-chloro-methoxybenzene                                                                       a                                            3-fluoro-2-methoxyphenyl                                                                       3-fluoro-2-hydroxybenzaldehyde                                                                b                                            5-chloro-3-fluoro-2-methoxyphenyl                                                              4-chloro-2-fluorophenol                                                                       b, a                                         3-chloro-5-fluoro-2-methoxyphenyl                                                              2-chloro-4-fluoro-methoxybenzene                                                              a                                            3,5-chloro-2-methoxyphenyl                                                                     2,4-dichloro-methoxybenzene                                                                   a                                            4-methoxyphenyl  --              commercial                                   2-thienyl        --              commercial                                   2-methoxynaphthyl                                                                              --              commercial                                   3-thienyl        --              commercial                                   2,5-difluorophenyl                                                                             --              commercial                                   2,4-dimethoxyphenyl                                                                            --              commercial                                   2,4-dichloro-6-methoxyphenyl                                                                   3,5-dichloro-methoxybenzene                                                                   a                                            2,6-dichloro-4-methoxyphenyl                                                                   3,5-dichloro-methoxybenzene                                                                   a                                            3,4-dichloro-2-methoxyphenyl                                                                   2,3-dichloro-methoxybenzene                                                                   a                                            2,3-dimethoxyphenyl                                                                            --              commercial                                   5-bromo-2-methoxy-3-methylphenyl                                                               2-methyl-methoxybenzene                                                                       c, a                                         2-cyclopentyloxyphenyl                                                                         2-hydroxybenzaldehyde                                                                         d                                            2-cyclopentyloxy-5-methoxyphenyl                                                               2-hydroxy-5-methoxybenzaldehyde                                                               d                                            5-t-butyl-2-methoxyphenyl                                                                      4-t-butylphenol e, a                                         5-s-buytl-2-methoxyphenyl                                                                      4-s-butylphenol e, a                                         5-fluoro-2-methoxypheny                                                                        4-fluoro-methoxybenzene                                                                       a                                            2-acetamidophenyl                                                                              2-aminobenzaldehyde                                                                           f                                            2-methoxyphenyl  --              commercial                                   5-isopropyl-2-methoxyphenyl                                                                    4-isopropyl-methoxybenzene                                                                    a                                            5-n-propyl-2-methoxyphenyl                                                                     4-n-propylphenol                                                                              e, a                                         4,5-dimethyl-2-methoxyphenyl                                                                   3,4-dimethylphenol                                                                            e, a                                         5-heptyl-2-methoxyphenyl                                                                       4-heptylphenol  e, a                                         2-heptyloxy-5-methoxyphenyl                                                                    4-heptyloxyphenol                                                                             e, a                                         5-heptyloxy-2-methoxyphenyl                                                                    4-heptyloxyphenol                                                                             e, a                                         2-(2,2,2-trifluoroethoxy)phenyl                                                                2-chlorobenzonitrile                                                                          g, h                                         quinolin-8-yl    8-methylquinoline                                                                             i                                            5-hydroxy-2-methoxyphenyl                                                                      4-methoxyphenol a                                            2-methoxy-5-phenylphenyl                                                                       4-phenylphenol  e, a                                         4-amino-5-chloro-2-methoxyphenyl                                                               4-amino-5-chloro-2-methoxybenzoic                                                             j                                                             acid                                                         2-hydroxy-5-trifluoromethoxyphenyl                                                             2-methoxy-5-trifluoromethoxybenz-                                                             k                                                             aldehyde                                                     5-t-butyl-2-hydroxyphenyl                                                                      4-t-butylphenol a                                            3-trifluoromethoxyphenyl                                                                       --              commercial                                   5-chloro-2-(2,2,2-                                                                             2,6-dichlorobenzonitrile                                                                      g, h                                         trifluoroethoxy)phenyl                                                        5-carbomethoxy-2-methoxyphenyl                                                                 5-carbomethoxy-2-hydroxybenzalde-                                                             e                                                             hyde                                                         5-t-butyl-2-trifluoromethoxyphenyl                                                             trifluoromethoxybenzene                                                                       l, m                                         5-n-butyl-2-methoxyphenyl                                                                      4-n-butylphenol e, a                                         2-ethoxy-5-trifluoromethoxyphenyl                                                              4-trifluoromethoxyphenol                                                                      n, a                                         2-methoxy-5-phenoxyphenyl                                                                      4-phenoxyphenol e, a                                         5-ethyl-2-methoxyphenyl                                                                        4-ethyl-methoxybenzene                                                                        a                                            2-difluoromethoxy-5-                                                                           2-hydroxy-5-trifluoromethoxyben-                                                              p                                            trifluoromethoxyphenyl                                                                         zaldehyde                                                    5-isopropyl-2-(2,2,2-                                                                          4-isopropyl-iodobenzene                                                                       g, a                                         trifluoroethoxy)phenyl                                                        2-isopropoxy-5-trifluoromethoxyphenyl                                                          4-trifluoromethoxyphenol                                                                      q, a                                         5-dimethylamino-2-methoxyphenyl                                                                5-amino-2-hydroxybenzaldehyde                                                                 e, r                                         5-t-butyl-2-difluoromethoxyphenyl                                                              4-t-butylphenol a, p                                         2-methoxy-5-(N-  5-amino-2-hydroxybenzoic acid                                                                 s                                            methylsulfonamido)phenyl                                                      5-methylmercapto-2-methoxyphenyl                                                               4-methylthiophenol                                                                            e, a                                         2-methoxy-5-methylaminomethylphenyl                                                            2-methoxy-5-(N-methylcarbox-                                                                  t                                                             amido)benzaldehyde                                           2-methoxy-5-methylsulfoxyphenyl                                                                5-methylmercapto-2-                                                                           u                                                             methoxybenzaldehyde                                          2-methoxy-5-methylsulfonylphenyl                                                               5-methylmercapto-2-                                                                           u                                                             methoxybenzaldehyde                                          2,5-bis(difluoromethoxy)phenyl                                                                 2,5-dihydroxybenzaldhyde                                                                      p                                            2-difluoromethoxy-5-                                                                           5-amino-2-hydroxybenzaldehyde                                                                 r, p                                         dimethylaminophenyl                                                           2-difluoromethoxy-5-isopropylphenyl                                                            4-isopropylphenol                                                                             a, p                                         2-difluoromethoxy-5-methylthiophenyl                                                           4-methylthiophenol                                                                            e, m, k, p                                   2-difluoromethoxy-5-nitrophenyl                                                                2-hydroxy-5-nitrobenzaldehyde                                                                 p                                            5-dimethylamino-2-(2,2,2-                                                                      2-chloro-5-nitrobenzonitrile                                                                  g, r, h                                      trifluoroethoxy)pheny                                                         5-acetamido-2-(2,2,2-                                                                          5-nitro-2-(2,2,2-                                                                             v, f, h                                      trifluoroethoxy)phenyl                                                                         trifluoroethoxy)benzonitrile                                 2-difluoromethoxy-5-ethylphenyl                                                                4-ethyl-methoxybenzene                                                                        a, k, p                                      5-chloro-2-difluoromethoxyphenyl                                                               5-chloro-2-hydroxy-benzaldehyde                                                               p                                            2-trifluoromethoxyphenyl                                                                       --              commercial                                   2-methoxy-5-trifluoromethoxyphenyl                                                             4-trifluoromethoxyphenol                                                                      e, a                                         __________________________________________________________________________     *Reagents for Preparation of R.sup.1 CHO From Standard Routes                 a) Cl.sub.2 CHOCH.sub.3, TiCl.sub.4                                           b) dimethylsulfate                                                            c) Br.sub.2 /HOAc                                                             d) cyclopentyl bromide                                                        e) methyl iodide                                                              f) acetyl chloride                                                            g) NaOCH.sub.2 CF.sub.3                                                       h) Raney nickel, HCO.sub.2 H                                                  i) SeO.sub.2                                                                  j) 1) carbonyldiimdazole, 2) N,Odimethylhydroxylamine, 3)                     diisolbutylaluminum hydride                                                   k) BBr.sub.3                                                                  l) tbutyl chloride/AlCl.sub.3                                                 m) Cl.sub.2 CHOCH.sub.3 /AlCl.sub.3                                           n) ethyl iodide                                                               p) ClF.sub.2 CH                                                               r) isopropyl bromide                                                          r) H.sub.2, Pd/C, HCHO                                                        s) 1) methanol/HCl, 2) methylsulfonyl chloride, 3) methyl iodide, 4)          diisobutylauminum hydride, 5) MnO.sub.2                                       t) borane methylsulfide complex                                               u) monoperoxyphthalic acid, magnesium salt hexahydrate                        v) H.sub.2 --Pd/BaSO.sub.4                                               

EXAMPLE 1 (+)-(2S,3S)-3-Amino-2-phenylpiperidine

In a bottle were placed 9 g of 10% palladium-carbon, 180 ml of methanol,275 ml of ethanol, 6.5 ml of concentrated hydrochloric acid and 9 g ofthe hydrochloride salt of(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine. The mixture wasshaken under hydrogen (40 p.s.i.) overnight, 9 g of additional catalystwere added to the system and the mixture was shaken under hydrogen for 1day. The mixture was diluted with water (250 mL), filtered throughdiatomaceous earth (Celite (trademark)) and the Celite was rinsed wellwith water. The filtrate was concentrated to a volume of ca. 600-700 mL,made basic with concentrated aqueous sodium hydroxide and extracted withchloroform, and the chloroform extracts were dried (sodium sulfate) andconcentrated to obtain 4.4 g of the title compound as a colorless oil.

α!_(D) (HCl Salt)=+62.8° (c=0.46, methanol (CH₃ OH)).

¹ H NMR (CDCl₃) δ1.68 (m, 4H), 2.72 (m, 1H), 2.94 (broad s, 1H), 3.16(m, 1H), 3.80 (d, 1H, J=3), 7.24 (m, 5H).

HRMS Calc'd for C₁₁ H₁₆ N₂ :176.1310. Found: 176.1309. Calc'd for C₁₁H₁₆ N₂.2HCl.1/3H₂ O: C, 51.78; H, 7.36; N, 10.98. Found: C, 51.46; H,7.27; N, 10.77.

EXAMPLE 2 (+)-(2S,3S)-3-(2,5-Dimethoxybenzylamino)-2-phenylpiperidine

Under a nitrogen atmosphere in a round-bottom flask were placed 600 mg(3.4 mmol) of (+)-(2S,3S)-3-amino-2-phenylpiperidine, 8 ml of aceticacid and 622 mg (3.7 mmol) of 2,5-dimethoxybenzaldehyde, and the mixturewas stirred for 30 minutes. To the system were added 1.58 g (7.5 mmol)of sodium triacetoxyborohydride, and the mixture was stirred at roomtemperature overnight. The mixture was concentrated, basified with 1Maqueous sodium hydroxide and extracted with methylene chloride. Themethylene chloride extracts were washed with water and extracted with 1Maqueous hydrochloric acid. The hydrochloric acid extracts were basifiedwith 1M aqueous sodium hydroxide and extracted with methylene chloride.The methylene chloride extracts were dried (sodium sulfate) andconcentrated to obtain 528 mg of colorless oil. The oil was dissolved inmethylene chloride, and ether saturated with hydrogen chloride was addedto the solution. The resulting white solid was collected by filtrationand stirred in isopropanol at 60° C. for 2 hours. Filtration afforded414 mg of the title compound as its hydrochloride. Additional material(400 mg) was obtained by extracting the initial basic layer withadditional methylene chloride, drying (sodium sulfate) andconcentration. α!_(D) (HCl salt)=+60.5° (c=0.58, CH₃ OH).

¹ H NMR (CDCl₃) δ1.38 (m, 1H), 1.58 (m, 1H) 1.88 (m, 1H), 2.13 (m, 1H),2.78 (m, 2H), 3.25 (m, 1H), 3.36 (d, 1H, J=18), 3.44 (s, 3H), 3.62 (d,1H, J=18), 3.72 (s, 3H), 3.88 (d, 1H, J=3), 6.62 (m, 3H), 7.24 (m, 5H).

Mass spectrum: m/z 326(parent).

Calc'd for C₂₀ H₂₆ N₂ O₂.2HCl.0.25H₂ O: C,59.48; H, 7.11;N, 6.93. Found:C, 59.33; H, 6.91; N, 7.23.

EXAMPLE 3 Cis-3-amino2-phenylpiperidine

In a bottle were placed 2.65 g (15.6 mmol) of 3-amino-2-phenylpyridine,10.6 g of 5% platinum/carbon and 106 mL of 1.5 M HCl in methanol. Themixture was shaken under an atmosphere (ca. 40 p.s.i.) of hydrogen for2.5 hours. Water was added to the system, the mixture was filteredthrough a pad of diatomaceous earth and the pad was rinsed with ca. 700mL of water. The filtrate was made basic with solid sodium hydroxide andextracted with two portions of dichloromethane. The combined organicfractions were washed with water, dried (sodium sulfate) andconcentrated with a rotary evaporator to obtain 2.4 g of the titlecompound as a yellow oil.

Calc'd for C₁₁ H₁₆ N₂ O.0.25H₂ O: C, 73.08; H, 9.20; N, 15.89. Found: C,72.80; H, 9.46; N, 15.84.

The title compounds if Examples 4-23 and 25-81 were prepared from either(+)-(2S,3S)-3-amino-2-phenylpiperidine or the corresponding racemate byemploying the appropriate aldehyde and using a procedure similar to thatof Example 2.

EXAMPLE 4 Cis-3-(4,5-difluoro-2--methoxybenzylamino)-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.30 (m, 1H), 1.62 (m, 2H), 1.96 (m, 1H), 2.68 (m, 2H),3.18 (m, 2H), 3.32 (s, 3H), 3.44 (d, 1H, J=14), 3.82 (d, 1H, J=3), 6.38(dd, 1H, J=6,12), 6.66 (dd, 1H, J=8, 10), 7.16 (m, 5H).

HRMS Calc'd for C₁₉ H₂₂ N₂ F₂ O: 332.1697. Found 332.1698. Calc'd forC₁₉ H₂₂ N₂ OF₂.2HCl.0.85H₂ O: C, 54.25; H, 6.15; N, 6.66. Found: C,54.26; H, 5.84; N, 6.94.

EXAMPLE 5 Cis-3-(2-chloro-4-fluorobenzylamino)-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.44 (m, 1H), 2.06 (m, 1H), 2.78 (m, 2H), 3.24 (m, 1H),3.40 (d, 1H, J=12), 3.58 (d, 1H, J=12), 3.88 (d, 1H, J=3), 6.75 (m, 1H),6.92 (m, 2H), 7.26 (m, 5H).

HRMS Calc'd for C₁₈ H₂₀ N₂ ³⁵ ClF:318.1294. Found 318.1280.

EXAMPLE 6 Cis-3--(2-ethoxybenzylamino)-2phenylpiperidine

¹ H NMR (CDCl₃) δ1.10 (t, 3H, J=5), 1.40 (m, 1H), 1.62 (m, 1H), 1.90 (m,1H), 2.14 (m, 1H), 2.80 (m, 2H), 3.27 (m, 1H), 3.38 (d, 1H, J=15), 3.69(m, 3H), 3.86 (d, 1H, J=2), 6.64 (d, 1H, J=8), 6.78 (t, 1H, J=6), 6.94(d, 1H, J=6), 7.12 (t, 1H, J=8), 7.24 (m, 5H).

HRMS Calc'd for C₂₀ H₂₆ N₂ O:310.2041. Found: 310.2045.

EXAMPLE 7 Cis-3-(2-hydroxybenzylamino)2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.62 (m, 3H), 2.10 (m, 1H), 2.79 (m, 1H), 2.92 (m, 1H),3.20 (m, 1H), 3.48 (s, 2H), 3.82 (d, 1H, J=2), 6.72 (m, 3H), 7.08 (m,1H), 7.36 (m, 5H).

HRMS Calc'd for C₁₈ H₂₂ N₂ O:282.1732. Found: 282.1724. Calc'd for C₁₈H₂₂ N₂ O. 2HCl.2H₂ O: C, 55.26, H, 7.20; N, 7.16. Found: C, 55.13; H,7.12; N, 6.84.

EXAMPLE 8 Cis-3-(3,5-difluoro2-methoxybenzylamino)-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.45 (m, 1H), 1.64 (m, 1H), 1.86 (m, 1H), 2.08 (m, 1H),2.80 (m, 2H), 3.24 (m, 1H), 3.44 (d, 1H, J=15), 3.54 (d, 1H, J=15), 3.68(s, 3H), 3.90 (d, 1H, J=3), 6.57 (dd, 1H, J =8, 9), 6.69 (dd, 1H, J=9,12), 7.28 (m, 5H).

HRMS Calc'd for C₁₉ H₂₂ N₂ OF₂ 2:332.1698. Found: 332.1700. Calc'd forC₁₉ H₂₂ N₂ OF₂.2HCl:C, 56.30; H, 5.97; N, 6.92. Found: C, 56.17; H,5.84; N, 6.59.

EXAMPLE 9 Cis-3-(2-chloro-6-fluorobenzylamino)-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.40 (m, 1H), 1.66 (m, 1H), 1.90 (m, 1H), 2.15 (m, 1H),2.78 (m, 2H), 3.26 (m, 1H), 3.68 (d, 2H, J=18), 3.72 (d, 1H, J=18), 6.82(m, 1H), 7.04 (m, 2H), 7.22 (m, 5H).

HRMS Calc'd for C₁₈ H₂₀ N₂ ClF.2HCl.2/3H₂ O: C, 53.56; H, 5.83; N, 6.95.Found: C, 53.63; H, 5.53; N, 6.83.

EXAMPLE 10 (2S,3S)-3-(5-chloro-2methoxybenzylamino)-2-phenylpiperidine

Mp 275°-277° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.40 (m, 1H), 1.60 (m, 1H), 1.90 (m, 1H), 2.08 (m, 1H),2.79 (m, 2H), 3.26 (m, 1H), 3.36 (d, 1H, J=15), 3.45 (s, 3H), 3.60 (d,1H, J=15), 3.88 (d, 1H, J=3), 6.56 (d, 1H, J=8), 6.92 (d, 1H, J=3), 7.06(dd, 1H, J=3, 8), 7.28 (m, 5H).

Mass spectrum: m/z 330 (parent).

EXAMPLE 11 Cis-3-(5-chloro-2-methoxybenzylamino)-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.37 (m, 1H), 1.56 (m, 1H), 1.86 (m, 1H), 2.06 (m, 1H),2.76 (m, 2H), 3.23 (m, 1H), 3.32 (d, 1H, J=15), 3.42 (s, 3H), 3.58 (d,1H, J=15), 3.85 (d, 1H, J=3), 6.54 (d, 1H, J=8), 6.90 (d, 1H, J=3), 7.04(dd, 1H, J=3, 8), 7.24 (m, 5H).

EXAMPLE 12 Cis-3(2,5-dimethoxybenzylamino)-2-phenylpiperidine

M.p. 250°-252° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.28-1.40 (m, 1H), 1.48-1.92 (m, 2H), 2.02-2.14 (m,1H), 2.66-2.80 (m, 2H), 3.14-3.24 (m, 1H), 3.32 (d, 1H, J=18), 3.38 (s,3H), 3.56 (d, 1H, J=18), 3.66 (s, 3H), 3.83 (d, 1H, J=3), 6.48-6.62 (m,3H), 7.10-7.26 (m, 5H).

HRMS Calc'd for C₂₀ H₂₆ N₂ O₂ :326.1995. Found: 326.1959. Anal. Calc'dfor C₂₀ H₂₆ N₂ O₂.2HCl.0.3H₂ O:C, 59.34; H, 7.12; N, 6.92. Found: C,59.33; H, 6.96; N, 6.76.

EXAMPLE 13 Cis-3-(5-fluoro-2-methoxybenzylamino)-2-phenylpiperidine

M.p. 270°-272° C. (HCl salt).

HRMS Calc'd for C₁₉ H₂₃ FN₂ O:314.1791. Found: 314.1766. Anal. Calc'dfor C₁₉ H₂₃ FN₂ O.2HCl.0.5H₂ O:C, 57.58; H, 6.61; N, 7.07. Found: C,57.35; H, 6.36; N, 7.03.

¹ H NMR (CDCl₃) δ1.30-1.42 (m, 1H), 1.48-2.12 (m, 3H), 2.64-2.82 (m,2H), 3.12-3.26 (m, 1H), 3.32 (d, 1H, J=12), 3.42 (s, 3H), 3.56 (d, 1H,J=12), 3.84 (d, 1H, J=3), 6.53 (dd, 1H, J=5, 10), 6.64 (dd, 1H, J=3, 8),6.70-6.80 (m, 1H), 7.12-7.40 (m, 5H).

EXAMPLE 14 Cis-2-phenyl-3- 2-(prop-2-yloxy)benzylamino!piperidine

¹ H NMR (CDCl₃) δ1.00 (m, 6H), 1.30 (m, 1H), 1.70 (m, 2H), 2.10 (m, 1H),2.72 (m, 2H), 3.18 (m, 1H), 3.30 (m, 1H), 3.50 (m, 1H), 3.80 (br s, 1H),4.06 (m, 1H), 6.66 (m, 2H), 6.90 (m, 1H), 7.05 (m, 1H), 7.20 (m, 5H).

HRMS Calc'd for C₂₁ H₂₈ N₂ O:324.2197. Found: 324.2180. Calc'd for C₂₁H₂₈ N₂ O.2HCl.1.66H₂ O:C, 59.02; H, 7.85; N, 6.55. Found: C, 59.07; H,7.77; N, 6.69.

EXAMPLE 15 Cis-3-(3-fluoro-2-methoxybenzylamino)-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.40 (m, 1H), 1.60 (m, 1H), 1.86 (m, 1H), 2.08 (m, 1H),2.80 (m, 2H), 3.23 (m, 1H), 3.36 (m, 1H), 3.58 (m, 4H), 3.88 (m, 1H),6.80 (m, 3H), 7.26 (m, 5H).

HRMS Calc'd for C₁₉ H₂₃ FN₂ O:314.1794. Found: 314.1768. Calc'd for C₁₉H₂₃ FN₂ O.2HCl.1.5H₂ O:C, 55.08; H, 6.80; N, 6.76. Found: C, 54.89; H,6.48; N, 6.79.

EXAMPLE 16 Cis-3-(5-chloro-3-fluoro-2-methoxybenzylamino)-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.42 (m, 1H), 1.54 (m, 1H), 1.80 (m, 1H), 2.06 (m, 1H),2.78 (m, 2H), 3.20 (m, 1H), 3.42 (d, 1H, J=15), 3.58 (d, 1H, J=15), 3.64(s, 3H), 3.86 (m, 1H), 6.66 (d, 1H, J=9), 6.91 (d, 1H, J=9), 7.26 (m,5H).

HRMS Calc'd for C₁₉ H₂₂ FN₂ OCl:348.1401. Found: 348.1406.

EXAMPLE 17Cis-3-(3-chloro-5-fluoro-2-methoxybenzylamino)-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.44 (m, 1H), 1.58 (m, 1H), 1.80 (m, 1H), 2.06 (m, 1H),2.80 (m, 2H), 3.22 (m, 1H), 3.42 (d, 1H, J=18), 3.54 (d, 1H, J=18), 3.66(s, 3H), 3.88 (d, 1H, J=2), 6.55 (d, 1H, J=6), 6.92 (d, 1H, J=9), 7.26(m, 5H).

HRMS Calc'd for C₁₉ H₂₂ ClFN₂ O:348.1401. Found: 348.1411. Calc'd forC₁₉ H₂₂ ClFN₂ O.2HCl.0.25H₂ O:C, 53.53; H, 5.79; N, 6.57. Found: C,53.58; H, 5.60; N, 6.41.

EXAMPLE 18 Cis -3-(3,5-dichloro-2-methoxybenzylamino)-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.44 (m, 1H), 1.56 (m, 1H), 1.82 (m, 1H), 2.08 (m, 1H),2.80 (m, 2H), 3.20 (m, 1H), 3.50 (m, 2H), 3.64 (s, 3H), 3.88 (m, 1H),6.68 (s, 1H), 7.26 (m, 6H).

HRMS Calc'd for C₁₉ H₂₂ Cl₂ N₂ O:364.1105. Found: 364.1105. Calc'd forC₁₉ H₂₂ Cl₂ N₂ O.2HCl:C, 52.07; H, 5.52; N, 6.39. Found: C, 51.69; H,5.50; N, 6.32.

EXAMPLE 19 Cis-3-(4-Methoxybenzylamino)-2-phenylpiperidine

M.p. 264°-266° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.28-1.40 (m, 1H), 1.44-1.88 (m, 2H), 1.92-2.02 (m,1H), 2.64-2.84 (m, 2H), 3.10-3.22 (m, 1H), 3.19 (d, 1H, J=12), 3.39 (d,1H, J=12), 3.70 (s, 3H), 3.81 (d, 1H, J=3), 6.65 (d, 2H, J=8), 6.83 (d,2H, J=6), 7.12-7.28 (m, 5H).

HRMS Calc'd for C₁₉ H₂₄ N₂ O: 296.1885. Found: 296.1871. Calc'd for C₁₉H₂₄ N₂ O.2HCl.0.6H₂ O: C, 60.03; H, 7.21; N, 7.37. Found: 60.08; H,7.11; N, 7.45.

EXAMPLE 20 Cis-2-Phenyl-3-(thien-2-ylmethylamino)piperidine

M.p. 250°-252° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.30-1.40 (m, 1H), 1.46-1.52 (m, 1H), 1.68-1.86 (m,1H), 1.92-2.00 (m, 1H), 2.64-2.78 (m, 1H), 2.84-2.92 (m, 1H), 3.12-3.22(m, 1H), 3.44 (d, 1H, J=12), 3.54 (d, 1H, J=12), 3.81 (d, 1H, J=3), 6.53(d, 1H, J=4), 6.72-6.80 (m, 1H), 7.02 (d, 1H, J=6), 7.12-7.30 (m, 5H).

HRMS Calc'd for C₁₆ H₂₀ N₂ S:272.1373. Found: 272.1327. Calc'd for C₁₆H₂₀ N₂ S.2HCl.1.1H₂ O: C, 52.62; H, 6.67; N, 7.67. Found: C, 52.64; H,6.38; N, 7.65.

EXAMPLE 21 Cis-3 -(2-Methoxynapth-1-ylmethylamino)-2-phenylpiperidine

M.p. 222°-225° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.36-1.48 (m, 1H), 1.52-2.04 (m, 2H), 2.18-2.32 (m,1H), 2.68-2.82 (m, 1H), 2.90 (d, 1H, J=3), 3.18-3.28 (m, 1H), 3.64 (s,3H), 3.80 (d, 1H, J=12), 3.86 (d, 1H, J=4), 4.07 (d, 1H, J=12),7.02-7.32 (m, 8H), 7.57 (d, 1H, J=8), 7.60-7.70 (m, 2H).

HRMS Calc'd for C₂₃ H₂₆ N₂ O:346.2041. Found: 346.2043.

EXAMPLE 22 Cis-2-Phenyl-3-(thien-3-ylmethylamino)piperidine

M.p. 264°-267° C. (HCL salt).

¹ H NMR (CDCl₃) δ1.30-1.40 (m, 1H), 1.46-1.64 (m, 1H), 1.70-1.88 (m,1H), 1.92-2.02 (m, 1H), 2.68-2.78 (m, 1H), 2.80-2.88 (m, 1H), 3.14-3.22(m, 1H), 3.31 (d, 1H, J=12), 3.48 (d, 1H, J=12), 3.84 (d, 1H, J=3), 6.65(d, 1H, J=6), 6.72 (d, 1H, J=3), 7.04-7.10 (m, 1H), 7.14-7.28 (m, 5H).

HRMS Calc'd for C₁₆ H₂₀ N₂ S:272.1342. Found: 272.1364. Calc'd for C₁₆H₂₀ N₂ S.2HCl.0.6H₂ O:C, 53.96; H, 6.57; N, 7.87. Found: C, 53.97; H,6.25; N, 7.77.

EXAMPLE 23 Cis-3-(2,5-Difluorobenzylamino)-2-phenylpiperidine

M.p. 274°-276° C. (HCL salt).

¹ H NMR (CDCl₃) δ1.28-1.40 (m, 1H), 1.44-1.62 (m, 1H), 1.66-1.84 (m,1H), 1.90-2.00 (m, 1H), 2.64-2.76 (m, 2H), 2.10-3.20 (m, 1H), 3.32 (d,1H, J=12), 3.44 (d, 1H, J=12), 3.81 (d, 1H, J=3), 6.50-6.58 (m, 1H),6.62-6.78 (m, 2H), 7.10-7.26 (m, 5H).

HRMS Calc'd for C₁₈ H₂₀ F₂ N₂ :302.1590. Found: 302.1560. Calc'd for C₁₈H₂₀ F₂ N₂.2HCl.0.2H₂ O:C, 57.06; H, 5.96; N, 7.39. Found: C, 56.94; H,5.94; N, 7.37.

EXAMPLE 24 (2S,3S)-3-Amino-2-phenylpiperidine

In a bottle were placed 31 g of 10% palladium-carbon, 50 mL of water,300 mL of methanol, 450 mL of ethanol, 20 mL of concentrated aqueoushydrochloric acid and 15 g (0.04 mole) of the hydrochloride salt of(2S,3S)-3-(2-methoxybenzyl)amino-2-phenylpiperdine. The mixture wasshaken under hydrogen (40 p.s.i.) for 1 day and filtered through a padof diatomaceous earth. The pad was rinsed with 2N aqueous hydrochloricacid (HCl), water, ethanol and water and concentrated with a rotaryevaporator. Water was added to the residue and the mixture was madebasic using 4N aqueous sodium hydroxide (NaOH). The mixture wasextracted with four portions of dichloromethane, and the extracts weredried over magnesium sulfate (MgSO₄) and concentrated to obtain 2.23 gof the title compound. The aqueous fraction was concentrated to drynessand triturated with chloroform. Concentration of the chloroform solutionafforded an additional 4.15 g of title compound. The product obtained inthis manner had spectral properties identical to those of the product ofExample 1.

EXAMPLE 25 Cis-3-(2,4-dimethoxybenzyl)amino-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.38 (m, 1H), 1.65 (m, 1H), 1.9 (m, 2H), 2.15 (m, 1H),2.8 (m, 2H), 3.25 (m, 1H), 3.35 (d, 1H, J=15), 3.4 (s, 3H), 3.6 (d, 1H,J=15), 3.78 (s, 3H), 3.85 (d, 1H, J=3), 6.25 (d, 1H, J=3), 6.35 (dd, 1H,J=10, 3), 6.85 (d, 1H, J=10), 7.30 (m, 5H).

Mass spectrum m/z 326 (parent).

Anal. calc'd for C₂₀ H₂₆ N₂ O₂.2HCl:C, 60.14; H, 7.07, N, 7.02 Found: C,59.66; H, 7.11; N, 6.83.

EXAMPLE 26 Cis-3-(2,4 dichloro-6-methoxybenzyl)amino-2-phenylpiperidine

M.p. 256°-258° C. (HCl salt).

¹ H NMR (CDCl³) δ1.4 (m, 1H), 1.62 (m, 3H), 1.94 (m, 1H), 2.2 (m, 1H),2.68 (m, 1H), 2.76 (m, 1H), 3.2 (m, 1H), 3.38 (s, 3H), 3.4 (d, 1H,J=10), 3.64 (d, 1H, J=10), 3.84 (m, 1H), 6.48 (d, 1H, J=3), 6.84 (d, 1H,J=3), 7.2 (m, 5H).

Mass Spectrum m/z 364 (parent).

Anal. calc'd for C₁₉ H₂₂ Cl₂ N₂ O.2HCl: C, 52.07; H, 5.52; N, 6.39.Found: C, 51.81; H, 5.65; N, 6.17.

EXAMPLE 27 Cis-3-(2,6-dichloro-4-methoxybenzyl)amino-2-phenylpiperidine

M.p. 230°-240° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.4 (m, 1H), 1.6 (m, 3H), 1.92 (m, 1H), 2.16 (m, 1H),2.76 (m, 2H), 3.2 (m, 1H), 3.58 (d, 1H, J=12), 3.70 (s, 3H), 3.74 (d,1H, J=12), 3.86 (d, 1H, J=3), 6.66 (m, 2H), 7.2 (m, 5H).

Mass Spectrum m/z 364 (parent).

Anal. calc'd for C₁₉ H₂₂ Cl₂ NO₂.2HCl: C, 52.07; H, 5.52; N, 6.39.Found: C, 52.18; H, 5.46; N, 6.24.

EXAMPLE 28 Cis-3-(3,4-dichloro-2-methoxybenzyl)amino-2-phenylpiperidine

M.p. 246°-248° (HCl salt).

¹ H NMR (CDCl₃) δ1.4 (m, 1H), 1.65 (s, 2H), 1.9 (m, 1H), 2.05 (m, 2H),2.8 (m, 2H), 3.25 (m, 1H), 3.45 (d, 1H, J=15), 3.6 (d, 1H, J=15), 3.9(m, 4H), 6.65 (d, 1H, J=10), 6.90 (d, 1H, J=10), 7.3 (m, 5H).

HRMS Calc'd for C₁₉ H₂₂ Cl₂ N₂ O.2HCl: C, 52.07; H, 5.52; N, 6.39.Found: C, 51.58; H, 5.46; N, 6.26.

EXAMPLE 29 Cis-3-(2,3-dimethoxybenzyl)amino-2-phenylpiperidine

M.p. 238°-240° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.44 (m, 1H), 1.6 (m, 1H), 2.00 (m, 2H), 2.8 (dt, 2H,J=12, 3), 2.92 (m, 1H), 3.26 (m, 1H), 3.42 (d, 1H, J=10), 3.52 (s, 3H),3.53 (d, 1H, J=10), 3.78 (s, 3H), 3.84 (m, 1H), 3.90 (d, 1H, J=3), 6.52(d, 1H, J=10), 6.72 (d, 1H, J=10), 6.84 (d, 1H, J=10), 7.82 (m, 5M).

HRMS Calc'd for C₂₀ H₂₆ N₂ O₂ : 326.2058. Found: 326.1991.

Anal. calc'd for C₂₀ H₂₆ N₂ O₂.2HCl.1/2 H₂ O: C, 58.82; H, 7.16; N,6.86. Found C, 58.63; H, 7.26; N, 6.81.

EXAMPLE 30Cis-3-(5-bromo-2-methoxy-3-methylbenzyl)amino-2-phenylpiperidine

M.p. 236°-238° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.44 (m, 1H), 1.64 (m, 1H), 1.90 (m, 1H), 2.16 (s, 3H),2.80 (m, 2H), 3.26 (m, 1H), 3.36 (d, 1H, J=12), 3.43 (s, 1H), 3.52 (d,1H, J=12) 3.90 (m, 1H), 6.92 (s, 1H), 7.10 (s, 1H), 7.34 (m, 5H).

HRMS calc'd for C₂₀ H₂₅ BrN₂ O: 388.1144. Found: 388.1153.

EXAMPLE 31 (2S,3S)-3-(2,4-dimethoxybenzyl)amino-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.4 (m, 1H), 1.58 (m, 1H), 1.94 (m, 2H), 2.1 (m, 1H),2.8 (m, 2H), 3.28 (m, 1H), 3.34 (d, 1H, J=15), 3.38 (s, 3H), 3.64 (d,1H, J=15)), 3.76 (s, 3H), 3.88 (d, 1H, J=3), 6.24 (d, 1H, J=3), 6.30(dd, 1H, J=10, 3), 6.86 (d, 1H, J=10), 7.26 (m, 5H).

HRMS Calc'd for C₂₀ H₂₆ N₂ O₂ : 326.1988: Found: 326.1986.

Anal. calc'd for C₂₀ H₂₆ N₂ O₂.2HCl1/4H₂ O: C, 59.48; H, 7.11; N, 6.94.Found: C, 59.40; H, 6.96; N, 6.95.

EXAMPLE 32 (2S,3S)-3-(2-Cyclopentyloxybenzyl)amino-2-phenylpiperidine

M.p. 230°-232° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.75 (m, 13H), 2.14 (m, 1H), 2.80 (dt, 2H, J=12, 3),2.90 (m, 1H), 3.28 (m, 1H), 3.36 (d, 1H, J=15), 3.60 (d, 1H, J=15), 3.88(broad s, 1H), 4.58 (m, 1H), 6.74 (m, 2H), 6.84 (d, 1H, J=10), 7.12 (m,1H), 7.30 (m, 5H).

HRMS calc'd for C₂₃ H₄₀ N₂ O: 350.2351. Found: 350.2332.

Anal. calc'd for C₂₃ H₃₀ N₂ O.2HCl.2H₂ O: C; 60.12; H, 7.33; N, 6.10.Found C, 59.10; H, 7.19; N, 6.09.

EXAMPLE 33(2S,3S)-3-(2-Cyclopentyloxy-5-methoxybenzyl)amino-2-phenylpiperidine

M.p. 217°-219° C. (MCl salt).

¹ H NMR (CDCl₃) δ1.66 (m, 13H), 2.14 (m, 1H), 2.82 (dt, 2H, J=12, 3),2.92 (m, 1H), 3.14 (m, 2H), 3.54 (d, 1H, J=15), 3.72 (s, 3H), 3.90 (d,1H, J=15), 4.50 (m, 1H), 6.64 (m, 3H), 7.30 (m, 5H).

HRMS calc'd for C₂₄ H₃₂ N₂ O₂ : 380.2456. Found: 380.2457.

Anal. calc'd for C₂₄ H₃₂ N₂ O₂.2HCl.H₂ O: C, 60.14; H, 7.70; N, 5.94.Found C, 61.05; H, 7.67; N, 5.92.

EXAMPLE 34(2S,3S)-3-(5-tert-Butyl-2-methoxybenzyl)amino-2-phenylpiperidine

M.p. 262°-264° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.22 (s, 9H), 1.38 (m, 2H), 1.90 (m, 1H), 2.14 (m, 1H),2.80 (m, 2H), 3.26 (m, 1H), 3.36 (d, 1H, J=15), 3.44 (s, 3H), 3.62 (d,1H, J=15), 3.86 (d, 1H, J=3), 6.60 (d, 1H, J=10), 7.00 (d, 1H, J=3),7.12 (m, 1H), 7.26 (m, 5H).

HRMS calc'd for C₂₃ H₃₂ N₂ O: 352.2507. Found: 352.2512.

Anal. calc'd for C₂₃ H₃₂ N₂ O. 2HCl.0.5H₂ O: C, 63.58; H, 8.12; N, 6.45.Found C, 63.75; H, 8.00; N, 6.42.

EXAMPLE 35(2S,3S)-3-(5-sec-Butyl-2-methoxybenzyl)amino-2-phenylpiperidine

M.p. 260°-263° C. (HCl salt).

¹ H NMR (CDCl₃) δ0.8 (2t, 3H, J=6), 1.16 (2d, 3H, J=7), 1.5 (m, 4H), 1.9(m, 1H), 2.12 (m, 1H), 2.46 (m, 1H), 2.8 (m, 3H), 3.28 (m, 1H), 3.42 (d,1H, J=15), 3.44 (s, 3H), 3.66 (d, 1H, J=15), 3.90 (d, 1H, J=3), 6.60 (d,1H, J=10), 6.78 (broad s, 1H), 6.92 (d, 1H, J=10), 7.3 (m, 5H).

HRMS calc'd for C₂₃ H₃₂ N₂ O: 352.2507. Found: 352.2525. Anal. calc'dfor C₂₃ H₃₂ N₂ O.2HCl.H₂ O: C, 62.29; H, 8.18; N, 6.32. Found C, 62.95;H, 7.62; N, 6.61.

EXAMPLE 36 (2S,3S)-3-(5-Fluoro-2-methoxybenzylamino)-2-phenylpiperidine

M.p.>270° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.38 (m, 1H), 1.56 (m, 1H), 1.90 (m, 1H), 2.06 (m, 1H),2.66 (m, 2H), 3.26 (m, 1H), 3.30 (d, 1H, J=15), 3.38 (s, 3H), 3.56 (d,1H, J=15), 3.86 (d, 1H, J=3), 6.52 (m, 1H), 6.64 (dd, 1H, J=10, 3), 6.70(dt, 1H, J=10, 3), 7.24 (m, 5H).

Anal. calc'd for C₁₉ H₂₃ FN₂ O.5HCl.0.75H₂ O: C, 57.57; H, 6.61; N,7.06. Found: C, 57.83, H, 6.31; N, 7.06.

EXAMPLE 37(2S,3S)-3-(4.5-Difluoro-2-methoxybenzyl)amino-2-phenylpiperdine

¹ H NMR (CDCl₃) δ1.36 (m, 1H), 1.55 (m, 1H), 1.84 (m, 1H), 2.02 (m, 1H),2.72 (m, 2H), 3.20 (m, 1H), 3.26 (d, 1H, J=14), 3.42 (s, 3H), 3.52 (d,1H, J=14), 3.84 (d, 1H, J=3), 6.42 (dd, 1H, J=6, 12), 6.70 (dd, 1H, J=8,10), 7.20 (m, 5H).

Anal. calc'd for C₁₉ H₂₂ F₂ N₂ O.2HCl.0.55H₂ O: C, 54.96; H, 6.09; N,6.75. Found C, 54.65, H, 5.69; N, 6.74.

EXAMPLE 38 (2S,3S)-3-(2-Acetamidobenzyl)amino-2-phenylpiperidine

M.p. 187°-195° C. (HCl salt).

¹ H NMR (CDCl₃) δ1.52 (m, 1H), 1.61 (s, 3H), 1.70 (m, 1H), 2.10 (m, 2H),2.80 (m, 2H), 3.18 (m, 1H), 3.32 (d, 1H, J=16), 3.54 (d, 1H, J=16), 3.89(d, 1H, J=3), 6.88 (m, 2H) 7.26 (m, 7H).

HRMS calc'd for C₂₀ H₂₅ N₃ O:323.1997. Found: 323.1972.

EXAMPLE 39 (2S,3S)-3-(2-Methoxybenzyl)amino-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.36 (m, 1H), 1.54 (m, 1H), 2.0 (m, 2H), 2.78 (m, 2H),3.23 (m, 1H), 3.36 (d, 1H, J=14), 3.41 (s, 3H), 3.63 (d, 1H, J=14), 3.83(broad s, 1H), 6.61 (d, 1H, J=8), 6.74 (t, 1H, J=7), 6.91 (d, 1H, J=7),7.08 (t, 1H, J=8), 7.12 (m, 5H).

EXAMPLE 40 (2S,3S)-3-(2-Methoxybenzyl)amino-2-phenylpiperidine

M.P. 257°-259° C. (dec.)

¹ H NMR (free base; CDCl₃) δ1.32 (m, 1H), 1.50 (m, 1H), 1.82 (m, 1H),2.04 (m, 1H), 2.30 (s, 3H), 2.72 (m, 2H), 3.18 (m, 1H), 3.26 (d, 1H,J=15), 3.36 (s, 3H), 3.54 (d, 1H, J=15), 3.80 (d, 1H, J=3), 6.52 (d, 1H,J=10), 6.90 (d, 1H, J=3), 7.04 (dd, 1H, J=3, 10), 7.2 (m, 5H).

HRMS calc'd for C₂₀ H₂₆ N₂ OS: 342.1760. Found: 342.1770.

Anal. calc'd for C₂₀ H₂₆ N₂ OS.2HCl.0.25H₂ O: C, 57.20; H, 6.84; N,6.67. Found: C, 57.35; H, 6,76; N, 6.61.

EXAMPLE41(2S,3S)-3-(2--Methoxy-5-methylsulfoxybenzylamino)-2-phenylpiperidinehydrochloride

M.P. 209° C. (dec).

¹ H NMR (free base; CDCl₃) δ1.40 (m, 1H), 1.56 (m, 1H), 1.90 (m, 1H),2.10 (m, 1H), 2.59, 2.62 (2S, 3H), 2.76 (m, 2H), 3.22 (m, 1H), 3.42 (m,1H), 3.49, 3.52 (2S, 3H), 3.66 (m, 1H), 3.86 (d, 1H, J=3), 6.76 (m, 1H),7.24 (m, 6H), 7.46 (m, 1H).

HRMS calc'd for C₂₀ H₂₇ N₂ O₂ S(M+1): 359.1787. Found: 359.1763.

EXAMPLE 42(2S,3S)-3-(2-Methoxy-5-methylsulfonylbenzylamino)-2-phenylpiperidinehydrochloride

M.P.>260° C.

¹ H NMR (free base; CDCl₃) δ1.40 (m, 1H), 1.58 (m, 1H), 1.88 (m, 1H),2.10 (m, 1H), 2.78 (m, 2H), 2.96 (s, 3H), 3.24 (m, 1H), 3.38 (d, 1H,J=15), 3.54 (s, 3H), 3.66 (d, 1H, J=15), 3.90 (d, 1H, J=3), 6.74 (d, 1H,J=10), 7.26 (m, 5H), 7.58 (d, 1H, J=3), 7.72 (d, 1H, J=10).

HRMS calc'd for C₂₀ H₂₆ N₂ O₃ S: 374.1658. Found: 374.1622.

EXAMPLE 43 (2S,3S)-3-(2-Methoxy5-phenoxybenzylamino)-2-phenylpiperidinehydrochloride

M.P.>250° C.

¹ H NMR (free base; CDCl₃) δ1.34 (m, 1H), 1.74 (m, 2H), 2.06 (m, 1H),2.76 (m, 2H), 3.22 (m, 1H), 3.32 (d, 1H, J=15), 3.44 (s, 3H), 3.60 (d,1H, J=15), 3.85 (d, 1H, J=3), 6.60 (d, 1H, J=9), 6.67 (d, 1H, J=3), 6.78(dd, 1H, J=6,9), 6.86 (d, 2H), 7.00 (t, 1H, J=6), 7.22 (m, 7H).

HRMS calc'd for C₂₅ H₂₈ N₂ O₂ : 388.2151. Found: 382.2137.

EXAMPLE 44(2S,3S)-3-(2-Methylmethylsulfonamido-benzylamino)-2-phenylpiperidinehydrochloride

¹ H NMR (free base; CDCl₃) δ1.42 (m, 1H), 1.74 (m, 2H), 2.12 (m, 1H),2.78 (m, 5H), 3.20 (s, 3H), 3.24 (m, 1H), 3.36 (d, 1H, J=15), 3.52 (s,3H), 3.64 (d, 1H, J=15), 3.89 (d, 1H, J=3), 6.64 (d, 1H, J=9), 6.98 (d,1H, J=3), 7.14 (dd, 1H, J=3, 9), 7.26 (m, 5H).

HRMS calc'd for C₂₁ H₂₉ N₃ O₃ S: 403.1992. Found: 403.1923.

Anal. calc'd for C₂₁ H₂₉ N₃ O₃ S.2HCl.1/3H₂ O: C, 52.28; H, 6.61; N,8.71. Found: C, 52.09; H, 6.63; N, 8.68.

EXAMPLE 45(2S,3S)-3-(2,2,2-Trifluoroethoxybenzylamino)--2-phenylpiperidinehydrochloride

M.P.>275° C.

¹ H NMR (free base; CDCl₃) δ1.44 (m, 1H), 1.62 (m, 1H), 1.90 (m, 1H),2.10 (m, 1H), 2.82 (m, 2H), 3.26 (m, 1H), 3.38 (d, 1H, J=15), 3.66 (d,1H, J=15), 3.92 (d, 1H, J=3), 4.06 (m, 2H), 6.66 (d, 1H, J=10), 6.94 (m,2H), 7.16 (m, 1H), 7.30 (m, 5H).

HRMS calc'd for C₂₀ H₂₄ F₃ N₂ O(M+1): 365.1835. Found: 385.1908.

Anal. calc'd for C₂₀ H₂₃ F₃ N₂ O.2HCl.1/3H₂ O: C, 54.19; H, 5.84; N,6.32. Found: C, 54.22; H, 5.57; N, 6.42.

EXAMPLE 46(2S,3S)-3-(5-Chloro-2-(2,2,2-trifluoroethoxy)benzylamino)-2-phenylpiperidinehydrochloride

M.P. 267°-269° C.

¹ H NMR (free base; CDCl₃) δ1.40 (m, 1H), 1.60 (m, 1H), 1.82 (m, 1H),2.02 (m, 1H), 2.76 (m, 2H), 3.20 (m, 1H), 3.28 (d, 1H, J=15), 3.52 (d,1H, J=15), 3.84 (d, 1H, J=3), 4.00 (m, 2H), 6.54 (d, 1H, J=10), 6.92 (d,1H, J=3), 7.04 (m, 1H), 7.24 (m, 5H).

HRMS calc'd for C₂₀ H₂₂ ClF₃ N₂ O: 398.1368. Found: 398.1352.

Anal. calc'd for C₂₀ H₂₂ ClF₃ N₂ O.2HCl: C, 50.91; H, 5.13; N, 5.94.Found: C, 50.89; H, 4.84; N, 5.93.

EXAMPLE 47 (2S,3S)-3-(3Trifluoromethoxybenzylamino)-2-phenylpiperidinehydrochloride

M.P.>275° C.

¹ H NMR (free base; CDCl₃) δ1.4 (m, 1H), 1.54 (m, 1H), 1.80 (m, 1H),1.96 (m, 1H), 2.74 (m, 2H), 3.18 (m, 1H), 3.30 (d, 1H, J=15), 3.46 (d,1H, J=15), 3.82 (d, 1H, J=3), 6.80 (s, 1H), 6.84 (d, 1H, J=10), 6.92 (m,1H), 7.12 (m, 1H), 7.24 (m, 5H).

HRMS calc'd for C₁₉ H₂₁ F₃ N₂ O: 350.1601. Found: 350.1609.

Anal. calc'd for C₁₉ H₂₁ F₃ N₂ O.2HCl: C, 53.91; H, 5.48; N, 6.62.Found: C, 53.84; H, 5.07; N, 6.59.

EXAMPLE 48(2S,3S)-3-(5-t-Butyl-2trifluoromethoxybenzylamino)-2-phenylpiperidinehydrochloride

M.P. 262°-264° C.

¹ H NMR (free Base; CDCl₃) δ1.20 (s, 9H), 1.40 (m, 1H), 1.52 (m, 1H),1.84 (m, 1H), 2.06 (m, 1H), 2.80 (m, 2H), 3.22 (m, 1H), 3.38 (d, 1H,J=15), 3.58 (d, 1H, J=15), 3.86 (d, 1H, J=3), 6.98 (m, 1H), 7.12 (m,2H), 7.26 (m, 5H).

HRMS calc'd for C₂₃ H₂₉ F₃ N₂ O: 406.2225. Found: 406.2271.

Anal. calc'd for C₂₃ H₂₉ F₃ N₂ O.2HCl.1/3H₂ O: C, 56.92; H, 6.56; N,5.77. Found: C, 56.99; H, 6.41; N, 6.03.

EXAMPLE 49 (2S,3S)-3-5-Isopropyl-2-(2,2,2-trifluoroethoxy)benzylamino!-2-phenylpiperidinehydrochloride

M.P.>280° C. ¹ H NMR (free base; CDCl₃) δ1.12 (m, 6H), 1.4 (m, 1H), 1.62(m, 1H), 1.82 (m, 1H), 2.08 (m, 1H), 2.76 (m, 3H), 3.22 (m, 1H), 3.30(d, 1H, J=15), 3.38 (d, 1H, J=15), 3.82 (d, 1H, J=3), 4.02 (m, 2H), 6.56(d, 1H, J=10), 6.78 (d, 1H, J=3), 6.94 (m, 1H), 7.24 (m, 5H).

HRMS calc'd for C₂₃ H₃₀ F₃ N₂ O (M+1): 407.2303. Found: 407.2287.

Anal. calc'd for C₂₃ H₂₉ F₃ N₂ O.2HCl.1/2H₂ O: C, 56,55, H, 6.60; N,5.70. Found: C, 56.17: H, 6.39; N, 5.77.

EXAMPLE 50(2S,3S)-3-(2-Methoxy-5methylaminomethylbenzylamino)-2-phenylpiperidinehydrochloride

M.P. 242° C.

¹ H NMR (free base; CDCl₃) δ1.36 (m, 1H), 1.58 (m, 1H), 1.90 (m, 1H),2.10 (m, 1H), 2.38 (s, 3H), 2.80 (m, 2H), 3.22 (m, 1H), 3.42 (m, 4H),3.56 (s, 2H), 3.64 (d, 1H, J=15), 3.86 (d, 1H, J=3), 6.60 (d, 1H, J=10),6.86 (d, 1H, J=3), 7.02 (m, 1H), 7.26 (m, 5H).

HRMS calc'd for C₂₁ H₃₀ N₃ O (M+1): 340.2382. Found: 340.2400.

EXAMPLE 51 (2S,3S)-3-5-Dimethylamino-2-(2,2,2-trifluoroethoxy)benzylamino!-2-phenylpiperidinehydrochloride.

M.P. 250°-252° C.

¹ H NMR (free base; CDCl₃) δ1.40 (m, 1H), 1.60 (m, 1H), 1.86 (m, 1H),2.10 (m, 1H), 2.82 (m, 8H), 3.22 (m, 1H), 3.34 (d, 1H, J=15), 3.58 (d,1H, J=15), 3.88 (d, 1H, J=3), 4.00 (m, 2H), 6.42 (d, 1H, J=3), 6.50 (m,1H), 6.64 (d, 1H, J=10), 7.30 (m, 5H).

HRMS calc'd for C₂₂ H₂₈ F₃ N₃ O: 407.2178. Found: 407.2179.

EXAMPLE 52(2S,3S)-3-(2-Difluoromethoxy-5-methylmercaptobenzylamino)-2phenylpiperidinehydrochloride

M.P. 254°-256° C.

¹ H NMR (free base: CDCl₃) δ1.45 (m, 1H), 1.60 (m, 1H), 1.80 (m, 1H),2.10 (m, 1H), 2.40 (s, 3H), 2.80 (m, 2H), 3.20 (m, 1H), 3.30 (d, 1H,J=15), 3.55 (d, 1H, J=15), 3.90 (d, 1H, J=3), 6.10 (t, 1H, J=85), 6.95(m, 3H), 7.25 (m, 5H).

HRMS calc'd for C₂₀ H₂₅ Cl₂ F₂ N₂ OS(M+1): 379.1650. Found: 379.1668.

Anal. calc'd for C₂₀ H₂₄ N₂ OF₂ Cl₂.2HCl.1/4H₂ O: C, 52.69; H, 5.86; N,6.14. Found: C, 52.36; H, 5.86; N, 6.14.

EXAMPLE 53(2S,3S)-3-(5-sec-Butyl-2-methoxybenzyl)amino-2-phenylpiperidine

M.P. 260°-263° C. (HCl salt).

¹ H NMR (free base; CDCl₃) δ0.8 (2t, 3H, J=6), 1.16 (2d, 3H, J=7), 1.5(m, 4H), 1.9 (m, 1H), 2.12 (m, 1H), 2.46 (m, 1H), 2.8 (m, 3H), 3.28 (m,1H), 3.42 (d, 1H, J=15), 3.44 (s, 3H), 3.66 (d, 1H, J=15), 3.90 (d, 1H,J=3), 6.60 (d, 1H, J=10), 6.78 (broad s, 1H), 6.92 (d, 1H, J=10), 7.3(m, 5H).

HRMS calc'd for C₂₃ H₃₂ N₂ O: 352.2507. Found: 352.2525.

EXAMPLE 54(2S,3S)-3-(4-Amino-5-chloro-2methoxybenzyl)amino2-phenylpiperidinehydrochloride

M.P. 200°-203° C. (dec).

¹ H NMR (free base; CDCl₃) δ1.35 (m, 1H), 1.56 (m, 1H), 1.86 (m, 1H),2.05 (m, 1H), 2.75 (m, 2H), 3.22 (m, 2H), 3.36 (s, 3H), 3.48 (d, 1H,J=12), 3.84 (d, 1H, J=2), 6.08 (s, 1H), 6.78 (s, 1H), 7.24 (m, 5H).

HRMS calc'd for C₁₉ H₂₄ ClN₃ O: 345.1604. Found: 345.1589.

EXAMPLE 55 (2S,3S)-3-(2-Methoxy-5-phenylbenzylamino)-2-phenylpiperidinehydrochloride

M.P. 238°-339° C. (dec).

¹ H NMR (free base; CDCl₃) δ1.38 (m, 1H), 1.60 (m, 1H), 1.88 (m, 1H),2.12 (m, 1H), 2.80 (m, 2H), 3.23 (m, 1H), 3.45 (m, 4H), 3.70 (d, 1H,J=12), 3.86 (d, 1H, J=3), 6.70 (d, 1H, J=6), 7.34 (m, 12H).

HRMS calc'd for C₂₅ H₂₈ N₂ O: 372.2197. Found: 372.2172.

EXAMPLE 56 (2S,3S)-2-Phenyl-3-(quinolin-8-yl)methylpiperidinehydrochloride

M.P. 252°-253° C. (dec).

¹ H NMR (free base; CDCl₃) δ1.38 (m, 1H), 1.58 (m, 1H), 1.94 (m, 1H),2.17 (m, 1H), 2.78 (m, 2H), 3.24 (m, 1H), 3.83 (d, 1H, J=3), 3.96 (d,1H, J=15), 4.28 (d, 1H, J=15), 7.14 (m, 6H), 7.32 (m, 2H), 7.58 (t, 1H,J=4), 7.98 (d, 1H, J=6), 8.46 (m, 1H).

HRMS calc'd for C₂₁ H₂₃ N₃ : 317.1887. Found: 317.1883.

EXAMPLE 57(2S,3S)-3-(5-Heptyloxy-2methoxybenzyl)amino-2-phenylpiperidinehydrochloride

M.P. 230° C. (dec).

¹ H NMR (free base; CDCl₃) δ0.90 (m, 2H), 1.38 (m, 10H), 1.76 (m, 4H),2.12 (m, 1H), 2.80 (m, 2H), 3.26 (m, 1H), 3.38 (d, 1H, J=16), 3.42 (s,3H), 3.62 (d, 1H, J=15), 3.82 (t, 2H, J=6), 3.88 (d, 1H, J=3), 6.62 (m,3H), 7.28 (m, 5H).

HRMS calc'd for C₂₆ H₃₈ N₂ O₂ : 410.2928. Found: 410.2953.

EXAMPLE 58(2S,3S)-3-(2-Heptyloxy-5methoxybenzyl)amino-2-phenylpiperidinehydrochloride

M.P. 212°-213° C. (dec).

¹ H NMR (free base; CDCl₃) δ0.90 (m, 3H), 1.60 (m, 13H), 2.12 (m, 1H),2.80 (m, 2H), 3.26 (m, 1H), 3.36 (d, 1H, J=15), 3.62 (m, 6H), 3.86 (d,1H, J=3), 6.60 (m, 3H), 7.23 (m, 5H).

HRMS calc'd for C₂₆ H₃₈ N₂ O₂ : 410.2928. Found: 410.2912.

EXAMPLE 59 (2S,3S)-3-(5-Heptyl-2-methoxybenzyl)amino-2-phenylpiperidinehydrochloride

M.P. 242°-243° C. (dec).

¹ H NMR (free base; CDCl₃) δ0.88 (m, 3H), 1.60 (m, 13H), 2.14 (m, 1H),2.44 (t, 2H, J=6), 2.78 (m, 2H), 3.26 (m, 1H), 3.40 (m, 4H), 3.64 (d,1H, J=15), 3.86 (d, 1H, J=2), 6.58 (d, 1H, J=6), 6.75 (d, 1H, J=2), 6.92(d, 1H, J=6), 7.26 (m, 5H).

HRMS calc'd for C₂₆ H₃₈ N₂ O: 394.2977. Found: 394.3009.

EXAMPLE 60(2S,3S)-3-(2-Methoxy-5-n-propylbenzyl)amino-2-phenylpiperidinehydrochloride

M.P. 245°-247° C. (dec).

¹ H NMR (free base; CDCl₃) δ0.9 (t, 3H, J=10), 1.4 (m, 1H), 1.54 (m,2H), 1.92 (m, 1H), 2.14 (m, 1H), 2.44 (t, 2H, J=6), 2.80 (m, 2H), 3.26(s, 1H), 3.40 (d, 1H, J=15), 3.44 (s, 3H), 3.66 (d, 1H, J=15), 3.90 (s,1H), 6.56 (d, 1H, J=10), 6.76 (s, 1H), 6.92 (d, 1H, J=10), 7.26 (m, 5H).

HRMS calc'd for C₂₂ H₃₀ N₂ O: 338.2351. Found: 338.2339.

Anal. calc'd for C₂₂ H₃₀ N₂ O.2HCl.0.25 H₂ O: C, 63.57, H, 7.81; N,6.74. Found: C, 63.59; H, 7.66; N, 6.73.

EXAMPLE 61(2S,3)-3-(4,5-Dimethyl-2-methoxybenzyl)amino-2-phenylpiperidinehydrochloride

M.P. 269°-270° C.

¹ H NMR (free base; CDCl₃) δ1.40 (m, 1H), 1.60 (m, 1H), 1.96 (m, 2H),2.14 (s, 3H), 2.18 (s, 3H), 2.80 (m, 2H), 3.30 (m, 1H), 3.40 (d, 1H,J=15), 3.42 (s, 3H), 3.62 (d, 1H, J=15), 3.90 (d, 1H, J=3), 6.48 (s,1H), 6.70 (s, 1H), 7.28 (m, 5H).

HRMS calc'd for C₂₁ H₂₈ N₂ O: 324.2195. Found: 324.2210.

Anal. calc'd for C₂₁ H₂₈ N₂ O.2HCl.0.25H₂ O: C, 62.80; H, 7.60; N, 6.99.Found: C, 62.64; H, 7.31; N, 6.86.

EXAMPLE 62 (2S,3S)-3-(5-t-Butyl-2-hydroxybenzyl)amino-2-phenylpiperidinehydrochloride

M.P. 267°-269° C. (dec).

¹ H NMR (free base: CDCl₃) δ1.3 (s, 9H), 1.6 (m, 3H), 2.18 (m, 1H), 2.82(m, 1H), 2.98 (m, 1H), 3.22 (m, 1H), 3.44 (d, 1H, J=15), 3.56 (d, 1H,J=15), 3.92 (m, 1H), 6.70 (m, 2H), 7.14 (m, 1H), 7.40 (m, 5H).

HRMS Calc'd for C₂₂ H₃₀ N₂ O: 338.2351. Found: 338.2384.

EXAMPLE 63(2S,3S)-3-(5-Carbomethoxy-2-methoxybenzyl)amino-2-phenylpiperidinehydrochloride

M.P. 238°-240° C.

¹ H NMR (free base; CDCl₃) δ1.4 (m, 1H), 1.6 (m, 1H), 1.88 (m, 1H), 2.1(m, 1H), 2.75 (m, 2H), 3.2 (m, 1H), 3.35 (d, 1H, J=15), 3.45 (s, 3H),3.7 (d, 1H, J=15), 3.85 (m, 4H), 6.65 (d, 1H, J=10), 7.2 (m, 5H), 7.70(d, 1H, J=3), 7.85 (m, 1H).

HRMS calc'd for C₂₁ H₂₆ N₂ O₃ : 354.1937. Found: 354.1932.

EXAMPLE 64 (2S,3S)-3-(5-n-Butyl-2-methoxybenzyl)amino-2-phenylpiperidinehydrochloride

M.P. 252°-253° C.

¹ H NMR (free base; CDCl₃) δ0.88 (t, 3H, J=10), 1.38 (m, 3H), 1.56 (m,3H), 1.96 (m, 2H), 2.18 (m, 1H), 2.50 (t, 2H, J=10), 2.86 (m, 2H), 3.30(m, 1H), 3.44 (d, 1M, J=15), 3.48 (s, 3H), 3.68 (d, 1H, J=15), 3.82 (d,1H, J=3), 6.62 (d, 1H, J=10), 6.80 (s, 1H), 6.86 (d, 1H, J=10), 7.3 (m,5H).

HRMS calc'd for C₂₃ H₃₂ N₂ O: 352.2507. Found: 352.2509.

Anal. calc'd for C₂₃ H₃₂ N₂ O.2HCl.1/3H₂ O: C, 64.03; H, 8.09; N, 6.50.Found: C, 64.39; H, 7.90; N, 6.59.

EXAMPLE 65(2S,3S)-3-(5-Isopropyl-2-methoxybenzyl)amino-2-phenylpiperidinehydrochloride

M.P. 252°-254° C.

¹ H NMR (free base; CDCl₃) δ1.14 (d, 6H, J=6), 1.36 (m, 1H), 1.58 (m,1H), 1.88 (m, 1H), 2.1 (m, 1H), 2.76 (m, 3H), 3.24 (m, 1H), 3.36 (d, 1H,J=15), 3.42 (s, 3H), 3.60 (d, 1H, J=15), 3.86 (d, 1H, J=3), 6.56 (d, 1H,J=10), 6.80 (d, 1H, J=3), 6.84 (m, 1H), 7.24 (m, 5H).

HRMS calc'd for C₂₂ H₃₀ N₂ O: 338.2351. Found: 338.2377.

Anal. calc'd for C₂₂ H₃₀ N₂ O.2HCl.1/4H₂ O: C, 63.52; H, 7.88; N, 6.74.Found: C, 63.33; H, 7.64; N, 6.75.

EXAMPLE 66(2S,3S)-3-(2-Difluoromethoxy-5-N,N-dimethylaminobenzylamino)-2-phenylpiperidinehydrochloride

M.P. 243°-245° C. (dec).

¹ H NMR (free base; CDCl₃) δ1.44 (m, 1H), 1.72 (m, 2H), 2.10 (m, 1H),2.84 (m, 8M), 3.21 (m, 1H), 3.28 (d, 1H, J=15), 3.55 (d, 1H, J=15), 3.88(d, 1H, J=3), 6.08 (t, 1H, J=72), 6.36 (d, 1H, J=3), 6.46 (dd, 1H,J=3,9), 6.86 (d, 1H, J=9), 7.28 (m, 5H).

HRMS calc'd for C₂₁ H₂₇ F₂ N₃ O: 375.2122. Found: 375.2138.

Anal. calc'd for C₂₁ H₂₇ F₂ N₃ O.3HCl.1/2H₂ O: C, 51.07; H, 6.44; N,8.51. Found: C, 50.71; H, 6.08; N, 8.28.

EXAMPLE 67 (2S,3S)-3- 2,5bis-(difluoromethoxy)benzyl)amino!-2-phenylpiperidine hydrochloride

M.P. 238°-239° C.

¹ H NMR (free base; CDCl₃) δ1.64 (m, 3H), 2.04 (m, 1H), 2.76 (m, 2H),3.18 (m, 1H), 3.28 (d, 1H, J=12), 3.52 (d, 1H, J=12), 3.84 (d, 1H, J=3),6.12 (t, 1H, J=75), 6.40 (t, 1H, J=75), 6.75 (m, 2H), 6.94 (d, 1H, J=9),7.24 (m, 5H).

HRMS calc'd for C₂₀ H₂₂ F₄ N₂ O₂ : 398.1612. Found: 398.1591.

EXAMPLE 68(2S,3S)-3-(5-t-Butyl-2-difluoromethoxybenzylamino)-2-phenylpiperidinehydrochloride

M.P. 263°-264° C. (dec).

¹ H NMR (free base; CDCl₃) δ1.24 (s, 9H), 1.42 (m, 1H), 1.62 (m, 1H),1.80 (m, 1H), 2.10 (m, 1H), 2.80 (m, 2H), 3.24 (m, 2H), 3.58 (d, 1H,J=12), 3.87 (brs, 1H), 6.18 (t, 1H, J=72), 6.86 (d, 1H, J=6), 7.00 (brs,1H), 7.12 (m, 1H), 7.24 (m, 5H).

HRMS calc'd for C₂₃ H₃₀ F₂ N₂ O: 388.2321. Found: 388.2336.

EXAMPLE 69(2S,3S)-3-(5Dimethylamino-2-methoxybenzylamino)-2-phenylpiperidinehydrochloride

M.P.>275° C.

¹ H NMR (free base; CDCl₃) δ1.34 (m, 1H), 1.70 (m, 2H), 2.10 (m, 1H),2.76 (m, 8H), 3.20 (m, 1H), 3.34 (m, 4H), 3.56 (d, 1H, J=12), 3.82 (d,1H, J=2), 6.50 (m, 3H), 7.22 (m, 5H).

HRMS calc'd for C₂₁ H₂₉ N₃ O: 339.2306. Found: 339.2274.

Anal. calc'd for C₂₁ H₂₉ N₃ O .3HCl.H₂ O: C, 54.02; H, 7.34; N, 9.00.Found: C, 53.84; H, 7.55; N, 8.92.

EXAMPLE 70(2S,3S)-3-(2-Isopropoxy-5-trifluoromethoxybenzylamino)-2-phenylpiperidinehydrochloride

M.P. 245°-246° C. (dec).

¹ H NMR (free base: CDCl₃) δ1.08 (d, 3H, J=6), 1.12 (d, 3H, J=6), 1.40(m, 1H), 1.64 (m, 1H), 1.87 (m, 1H), 2.08 (m, 1H), 2.78 (m, 2H), 3.02(m, 1H), 3.34 (d, 1H, J=15), 3.51 (d, 1H, J=15), 3.85 (d, 1H, J=2), 4.28(m, 1H), 6.01 (d, 1H, J=9), 6.82 (m, 1H), 6.91 (m, 1H), 7.24 (m, 5H).

HRMS calc'd for C₂₂ H₂₇ F₃ N₂ O₂ : 408.2024. Found: 408.2019.

Anal. calc'd for C₂₂ H₂₇ F₃ N₂ O₂.2HCl: C, 54.89; H, 6.07, N, 5.82.Found: C, 54.50; H, 6.24; N, 5.78.

EXAMPLE 71(2S,3S)-3-(2-Difluoromethoxy-5-trifluoromethoxybenzylamino)-2-phenylpiperidinehydrochloride

M.P. 257°-259° C. (dec).

¹ H NMR (free base; CDCl₃) δ1.44 (m, 1H), 1.58 (m, 1H), 1.78 (m, 1H),2.03 (m, 1H), 2.78 (m, 2H), 3.20 (m, 1H), 3.32 (d, 1H, J=15), 3.54 (d,1H, J=15), 3.87 (d, 1H, J=2), 6.15 (t, 1H, J=72), 6.94 (m, 3H), 7.26 (m,5H).

HRMS calc'd for C₂₀ H₂₁ F₅ N₂ O₂ : 416.1523. Found: 416.1501.

Anal. calc'd for C₂₀ H₂₁ F₅ N₂ O₂.2HCl.1/3H₂ O: C, 48.50; H, 4.81; N,5.65. Found: C, 48.45; H, 4.57; N, 5.66.

EXAMPLE 72(2S,3S)-3-(2-Ethoxy-5-trifluoromethoxybenzylamino)-2-phenylpiperidinehydrochloride

M.P.>275° C. (dec).

¹ H NMR (free base; CDCl₃) δ1.13 (t, 3H, J=6), 1.38 (m, 1H), 1.70 (m,2H), 2.06 (m, 1H), 2.74 (m, 2H), 3.22 (m, 1H), 3.30 (d, 1H, J=15), 3.68(m, 3H), 3.84 (br s, 1H), 6.55 (d, 1H, J=9), 6.79 (br s, 1H), 6.90 (m,1H), 7.2 (m, 5H).

HRMS calc'd for C₂₁ H₂₅ F₃ N₂ O₂ : 394.1868. Found: 394.1875.

Anal. calc'd for C₂₁ H₂₅ F₃ N₂ O₂.2HCl: C, 53.97; H, 5.82; N, 6.00.Found: C, 53.85; H, 5.79; N, 5.95.

EXAMPLE 73 (2S,3S)-3-(5-Ethyl-2-methoxybenzylamino)-2-phenylpiperidinehydrochloride

¹ H NMR (free base, CDCl₃) δ1.16 (t, 3H, J=9), 1.36 (m, 1H), 1.57 (m,1H), 1.88 (m, 1H), 2.12 (m, 1H), 2.48 (q, 2H), 2.76 (m, 2H), 3.24 (m,1H), 3.38 (m, 4H), 3.60 (d, 1H, J=12), 3.86 (d, 1H, J=3), 6.57 (d, 1H,J=6), 6.74 (d, 1H, J=3), 6.92 (dd, 1H, J=3,6), 7.24 (m, 5H).

HRMS calc'd for C₂₁ H₂₈ N₂ O: 324.2202. Found: 324.2202.

EXAMPLE 74(2S,3S)-3-(2-Difluoromethoxy-5-nitrobenzylamino)-2-phenylpiperidinehydrochloride

¹ H NMR (free base; CDCl₃) δ1.50 (m, 1H), 1.66 (m, 1H), 1.98 (m, 2H),2.82 (m, 2H), 3.28 (m, 1H), 3.42 (d, 1H, J=15), 3.64 (d, 1H, J=15), 3.95(d, 1H, J=2), 6.30 (t, 1H, J=72), 7.08 (d, 1H, J=8), 7.30 (m, 5H), 8.04(m, 2H).

FAB HRMS calc'd for C₁₉ H₂₁ F₂ N₃ O₃ (M+1): 378.1629. Found: 378.1597.

EXAMPLE 75(2S,3S)-3-(2-Difluoromethoxy-5-isopropylbenzylamino)-2-phenylpiperidinehydrochloride

M.P. 245°-247° C. (dec).

¹ H NMR (free base; CDCl₃) δ1.19 (2d, 6H, J=7), 1.50 (m, 1H), 1.75 (m,2H), 2.12 (m, 1H), 2.83 (m, 3H), 3.25 (m, 1H), 3.35 (d, 1H, J=14), 3.60(d, 1H, J=14), 3.90 (d, 1H, J=3), 6.20 (t, 1H, J=75), 6.90 (m, 2H), 7.00(m, 1H), 7.30 (m, 5H).

HRMS calc'd for C₂₂ H₂₈ F₂ N₂ O: 374.2170. Found: 374.2207.

Anal. calc'd for C₂₂ H₂₈ F₂ N₂ O.2HCl.1/3H₂ O: C, 58.28; H, 6.67; N,6.18. Found: C, 58.17; H, 6.52; N, 6.17.

EXAMPLE 76 (2S,3S)-3-(2-Methoxy-5-hydroxybenzylamino)-2-phenylpiperidinehydrochloride

M.P. 239°-240° C. (dec).

¹ H NMR (free base; CDCl₃) δ1.42 (m, 1H), 1.64 (m, 1H), 1.90 (m, 1H),2.16 (m, 1H), 2.82 (m, 2H), 3.26 (m, 1H), 3.36 (d, 1H, J=15), 3.42 (s,3H), 3.58 (d, 1H, J=15), 3.92 (d, 1H, J=2), 6.37 (d, 1H, J=2), 6.52 (m,2H), 7.26 (m, 5H).

HRMS calc'd for C₁₉ H₂₄ N₂ O₂ : 312.1836. Found: 312.1865.

EXAMPLE 77(2S,3S)-3-(2-Methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidinehydrochloride

M.p.>250° C.

¹ H NMR (free base, CDCl₃) δ1.36 (s, 1H), 1.54 (m, 1H), 1.86 (m, 1H),2.06 (m, 1H), 2.76 (m, 2H), 3.22 (m, 1H), 3.32 (d, 1H, J=15), 3.48 (s,3H), 3.58 (d, 1H, J=15), 3.85 (d, 1H, J=3), 6.57 (d, 1H, J=9), 6.80 (d,1H, J=3), 6.92 (dd, 1H, J=3, 9), 7.22 (m, 5H).

HRMS calc'd for C₂₀ H₂₃ F₃ N₂ O₂ : 380.1711. Found: 380.1704.

Anal. calc'd for C₂₀ H₂₃ F₃ N₂ O₂.2HCl.0.2H₂ O: C 52.57, H 5.60, N 6.13.Found: C 52.58, H 5.40, N 5.97.

EXAMPLE 78(2S,3S)-3-(2-Hydroxy-5-trifluoromethoxybenzylamino)-2-phenylpiperidinehydrochloride

¹ H NMR (free base; CDCl₃) δ1.60 (m, 3H), 2.04 (m, 1H), 2.76 (m, 1H),2.88 (m, 1H), 3.18 (m, 1H), 3.42 (s, 2H), 3.90 (m, 1H), 6.52 (m, 1H),6.64 (d, 1H, J=9), 6.89 (m, 1H), 7.30 (m, 5H).

HRMS calc'd for C₁₉ H₂₁ F₃ N₂ O₂ : 366.1545. Found: 366.1562.

Anal. calc'd for C₁₉ H₂₁ F₃ N₂ O₂.2HCl.1/3H₂ O: C, 51.25; H, 4.90; N,6.29. Found: C, 51.30; H, 4.75; N, 6.22.

EXAMPLE 79 (2S,3S)-3-5-Acetamido-2-(2,2,2-trifluoroethoxy)benzylamino!-2-phenylpiperidinehydrochloride

M.P.>270° C.

¹ H NMR (free base; CDCl₃) δ1.46 (m, 1H), 1.82 (m, 1H), 2.08 (m, 1H),2.12 (s, 3H), 2.76 (m, 2H), 3.20 (m, 1H), 3.48 (d, 1H, J=15), 3.58 (d,1H, J=15), 3.82 (m, 1H), 4.08 (m, 2H), 6.44 (m, 1H), 6.58 (d, 1H, J=10),6.78 (m, 1H), 7.26 (m, 5H), 7.58 (m, 1H).

EXAMPLE 80(2S,3S)-3-(2-Difluoromethoxy-5-ethylbenzylamino)-2-phenylpiperidinehydrochloride

M.P. 254°-255° C.

¹ H NMR (free base; CDCl₃) δ1.12 (t, 3H, J=10), 1.36 (m, 1H), 1.44 (m,1H), 1.82 (m, 1H), 2.10 (m, 1H), 2.48 (q, 2H, J=10), 2.8 (m, 1H), 3.10(m, 1H), 3.34 (d, 1H, J=15), 3.58 (d, 1H, J=15), 3.9 (d, 1H, J=3), 6.12(t, 1H, J=85), 6.78 (s, 1H), 6.90 (m, 2H), 7.28 (m, 5H).

Anal. calc'd for C₂₁ H₂₆ F₂ N₂ O.2HCl: C, 58.19; H, 6.51; N, 6.47.Found: C, 57.90; H, 6.52; N, 6.64.

EXAMPLE 81(2S,3S)-3-(5-Chloro-2-difluoromethoxybenzylamino)-2-phenylpiperidinehydrochloride

M.P. 272°-274° C.

¹ H NMR (free base; CDCl₃) δ1.48 (m, 1H), 1.64 (m, 1H), 1.84 (m, 1H),2.08 (m, 1H), 2.84 (m, 2H), 3.24 (m, 1H), 3.34 (d, 1H, J=15), 3.56 (d,1H, J=15), 3.90 (d, 1H, J=3), 6.12 (t, 1H, J=70), 6.90 (d, 1H, J=10),7.02 (m, 1H), 7.12 (m, 1H), 7.3 (m, 5H).

Anal. calc'd for C₁₉ H₂₁ ClF₂ N₂ O.2HCl.1/3H₂ O: C, 51.20; H, 5.33; N,6.29. Found: C, 51.03, H, 5.32. N, 6.30.

EXAMPLE 82(2S,3S)-Phenyl-3-(2-trifluoromethoxybenzyl)aminophenylpiperidinehydrochloride

M.p. 231°-233° C.

¹ H NMR (free base, CDCl₃) δ1.40 (m, 1H), 1.60 (m, 1H), 1.84 (m, 1H),2.05 (m, 1H), 2.78 (m, 2H), 3.22 (m, 1H), 3.42 (d, 1H, J=15), 3.56 (d,1H, J=15), 3.86 (d, 1H, J=3), 7.08 (m, 4H), 7.24 (m, 5H). Mass spectrum:m/z 350 (parent).

Anal. calc'd for C₁₉ H₂₁ F₃ N₂ O.2HCl.0.25H₂ O: C 53.34, H 5.54, N 6.54.Found: C 53.19, H 5.40, N 6.54.

I claim:
 1. A process for preparing a compound of the formula ##STR14##wherein R² is thienyl, benzhydryl, naphthyl or phenyl optionallysubstituted with from one to three substituents independently selectedfrom chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbonatoms, (C₁ -C₁₀)alkyl optionally substituted with one or more halogroups, (C₁ -C₁₀)alkoxy and trifluoromethyl, comprising a selectivereduction via hydrogenation in the presence of a metal containingcatalyst of the compound of the formula ##STR15## wherein R² is asdefined above.
 2. A process according to claim 1, wherein the selectivereduction is carried out using sodium in a boiling alcohol.
 3. A processaccording to claim 1, wherein the selective reduction is carried outusing lithium aluminum hydride/aluminum trichloride.
 4. A processaccording to claim 1, wherein the selective reduction is an electrolyticreduction.
 5. A process according to claim 1, wherein the selectivereduction is carried out using hydrogen in the presence of a metalcontaining catalyst.
 6. A process according to claim 1, wherein themetal containing catalyst is selected from the group consisting ofpalladium, palladium on carbon, platinum, nickel, platinium oxide andrhodium.
 7. A process for preparing a compound of high enantiomericpurity of the formula ##STR16## wherein R¹ is aryl selected fromindanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl,pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, whereinone of said carbon atoms may optionally be replaced by nitrogen, oxygenor sulfur; wherein each of said aryl and heteroaryl groups mayoptionally be substituted with one or more substituents, and said (C₃-C₇)cycloalkyl may optionally be substituted with one or twosubstituents, said substituents being independently selected fromchloro, fluoro, bromo, iodo, nitro, (C₁ -C₁₀)alkyl optionallysubstituted with from one to three fluoro groups, (C₁ -C₁₀)alkoxyoptionally substituted with from one to three fluoro groups, amino, (C₁-C₁₀)alkyl-S--, ##STR17## (C₁ -C₁₀)alkyl-SO₂ --, phenyl, phenoxy, (C₁-C₁₀)alkyl-SO₂ NH--, (C₁ -C₁₀)alkyl-SO₂ NH--(C₁ -C₁₀)alkyl--, (C₁-C₁₀)alkylamino-di(C₁ -C₁₀)alkyl--, cyano, hydroxyl, cycloalkoxy having3 to 7 carbon atoms, (C₁ -C₆)-alkylamino, (C₁ -C₆)dialkylamino,##STR18## wherein the nitrogen atoms of said amino and (C₁-C₆)alkylamino groups may optionally be protected with an appropriateprotecting group; and R² is thienyl, benzhydryl, naphthyl or phenyloptionally substituted with from one to three substituents independentlyselected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7carbon atoms, (C₁ -C₁₀)alkyl optionally substituted with from one tothree fluoro groups and (C₁ -C₁₀)alkoxy optionally substituted with fromone to three fluoro groups, comprising reacting a compound of theformula ##STR19## wherein R² is defined as above, with either (a) acompound of the formula ##STR20## wherein R¹ is defined as above and Xis a leaving group, followed by treatment of the resulting amide with areducing agent, (b) a compound of the formula R¹ CHO, wherein R¹ isdefined as above, in the presence of a reducing agent, or (c) a compoundof the formula R¹ CH₂ X, wherein R¹ is defined as above and X is aleaving group.
 8. A process according to claim 7, wherein said compoundof the formula IV is reacted with said compound of the formula R¹ CHO inthe presence of a reducing agent.
 9. A process according to claim 8,wherein said reducing agent is sodium triacetoxyborohydride.
 10. Aprocess according to claim 8, wherein said reducing agent is sodiumcyanoborohydride.
 11. A process according to claim 8, wherein saidreaction is conducted in a lower alcohol solvent at a temperature fromabout -60° C. to about 50° C.
 12. A process according to claim 8,wherein said reaction is conducted in an acetic acid solvent at atemperature from about -60° C. to about 50° C.
 13. A process forpreparing a compound of the formula ##STR21## wherein R¹ is arylselected from indanyl, phenyl and naphthyl; heteroaryl selected fromthienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7carbon atoms, wherein one of said carbon atoms may optionally bereplaced by nitrogen, oxygen or sulfur; wherein each of said aryl andheteroaryl groups may optionally be substituted with one or moresubstituents, and said (C₃ -C₇)cycloalkyl may optionally be substitutedwith one or two substituents, said substituents being independentlyselected from chloro, fluoro, bromo, iodo, nitro, (C₁ -C₁₀)alkyloptionally substituted with from one to three fluoro groups, (C₁-C₁₀)alkoxy optionally substituted with from one to three fluoro groups,amino, (C₁ -C₁₀)alkyl-S--, ##STR22## (C₁ -C₁₀)alkyl-SO₂ --, phenyl,phenoxy, (C₁ -C₁₀)alkyl-SO₂ NH--, (C₁ -C₁₀)alkyl-SO₂ NH--(C₁-C₁₀)alkyl--, (C₁ -C₁₀)alkylamino-di(C₁ -C₁₀)alkyl--, cyano, hydroxyl,cycloalkoxy having 3 to 7 carbon atoms, (C₁ -C₆)alkylamino, (C₁-C₆)dialkylamino, ##STR23## wherein the nitrogen atoms of said amino and(C₁ -C₆) alkylamino groups may optionally be protected with anappropriate protecting group; and R² is thienyl, benzhydryl, naphthyl orphenyl substituted with from one to three substituents independentlyselected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7carbon atoms, (C₁ -C₁₀)alkyl optionally substituted with from one tothree groups and (C₁ -C₁₀)alkoxy optionally substituted with from one tothree fluoro groups;comprising reacting a compound of the formula##STR24## wherein R² is defined as above, with a compound of the formulaR¹ CHO, wherein R¹ is defined as above, in the presence of a dryingagent or using an apparatus designed to remove azeotropically the watergenerated, to produce an imine of the formula ##STR25## wherein R₁ andR₂ are defined as above, and reacting the imine with a reducing agent.14. A process according to claim 13, wherein the reducing agent issodium triacetoxyborohydride.
 15. A process according to claim 7,wherein said compound of formula I formed thereby is a compound whereinR¹ and R² are the same or different and each of R¹ and R² is phenyloptionally substituted with one or more substituents independentlyselected from chlorine, fluorine, (C₁ -C₆)alkyl optionally substitutedwith from one to three fluoro groups and (C₁ -C₆)alkoxy optionallysubstituted with from one to three fluoro groups.
 16. A processaccording to claim 7, wherein said compound of formula I formed therebyis a compound wherein R¹ is 2-methoxyphenyl and R² is phenyl.
 17. Aprocess according to claim 13, wherein said compound of formula I formedthereby is a compound wherein R¹ and R² are the same or different andeach of R¹ and R² is phenyl optionally substituted with one or moresubstituents independently selected from chlorine, fluorine, (C₁-C₆)alkyl optionally substituted with from one to three fluoro groupsand (C₁ -C₆)alkoxy optionally substituted with from one to three fluorogroups.
 18. A process according to claim 13, wherein said compound offormula I formed thereby is a compound wherein R¹ is 2-methoxyphenyl andR² is phenyl.
 19. A process according to claim 7, wherein said compoundof formula I formed thereby is a compound wherein R¹ is4,5-difluoro-2-methoxyphenyl and R² is phenyl.
 20. A process accordingto claim 13, wherein said compound of formula I formed thereby is acompound wherein R¹ is 4,5-difluoro-2-methoxyphenyl and R² is phenyl.21. A process according to claim 7, wherein said compound of formula Iformed thereby is a compound wherein R¹ is2-methoxy-5-trifluoromethylphenyl and R² is phenyl.
 22. A processaccording to claim 13, wherein said compound of formula I formed therebyis a compound wherein R¹ is 2-methoxy-5-trifluoromethylphenyl and R² isphenyl.
 23. A process according to claim 7, wherein said compound offormula I formed thereby is a compound wherein R¹ is 2,4-dimethoxyphenyland R² is phenyl.
 24. A process according to claim 13, wherein saidcompound of formula I formed thereby is a compound wherein R¹ is2,4-dimethoxyphenyl and R² is phenyl.
 25. A process according to claim7, wherein said compound of formula I formed thereby is a compoundwherein R¹ is 2,3-dimethoxyphenyl and R² is phenyl.
 26. A processaccording to claim 13, wherein said compound of formula I formed therebyis a compound wherein R¹ is 2,3-dimethoxyphenyl and R² is phenyl.
 27. Aprocess according to claim 7, wherein said compound of formula I formedthereby is a compound wherein R¹ is "5-chloro-2-methoxyphenyl" and R² isphenyl.
 28. A process according to claim 13, wherein said compound offormula I formed thereby is a compound wherein R¹ is"5-chloro-2-methoxyphenyl" and R² is phenyl.
 29. A process according toclaim 7, wherein said compound of formula I formed thereby is a compoundwherein R¹ is "3-chloro-2-methoxyphenyl" and R² is phenyl.
 30. A processaccording to claim 13, wherein said compound of formula I formed therebyis a compound wherein R¹ is "3-chloro-2-methoxyphenyl" and R² is phenyl.